Clinical Development of Antibacterial Drugs: Recent Progress and Future Outlook

Abstract

The growing burden of antibiotic resistance demands the development of new antibacterials, including those with novel targets and mechanisms of action. This review summarizes key antibacterials that were in clinical development from 2010 to 2026, highlighting their antibacterial classes, mechanisms of action, antibacterial spectrum, clinical applications, development status, and resistance concerns. Antibacterial development during this period encompasses improvements to established antibiotic classes, new β-lactam/β-lactamase inhibitor combinations, siderophore cephalosporins, antibiotic hybrids, antibody-antibiotic conjugates, narrow-spectrum antibacterials, and antibacterials with novel chemical scaffolds, targets, and mechanisms of action. Successful clinical translation, promising emerging antibacterials, and innovations in antibacterial design and delivery are discussed. Lessons from discontinued development programs, including barriers related to safety, efficacy, and emerging resistance, are also highlighted to inform future antibacterial design and clinical trials. Continued investment in antibacterial discovery, early assessment of resistance potential and safety, exploration of nontraditional treatments, application of machine learning and artificial intelligence-guided methods, antibiotic stewardship, and implementation of One Health approaches will be important for addressing the growing challenge of antibiotic resistance.

1. Introduction

The growing global burden of antibiotic-resistant bacterial infections, often referred to as a silent pandemic, demands the development of new antibacterial drugs with novel targets or mechanisms of action [1,2,3]. According to an in-depth global analysis of antibiotic resistance, more than 39 million deaths are projected to be attributable to antibiotic-resistant bacterial infections between 2025 and 2050 [1]. Staphylococcus aureus, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Streptococcus pneumoniae, and Pseudomonas aeruginosa are the six leading pathogens contributing to the global burden of antibiotic resistance [1]. Reflecting the urgent need to address antibiotic resistance, the 2024 World Health Organization (WHO) Bacterial Priority Pathogens List categorizes antibiotic-resistant bacterial pathogens into critical, high, and medium priority groups to guide research and development of new antibacterial interventions [4]. Among the antibiotic-resistant pathogens prioritized by the WHO are Enterobacterales (including E. coli and K. pneumoniae), A. baumannii, Mycobacterium tuberculosis, S. aureus, P. aeruginosa, Neisseria gonorrhoeae, S. pneumoniae, and Haemophilus influenzae [4], underscoring the need for new antibacterials against diverse bacterial pathogens.

The modern antibiotic era began with Alexander Fleming’s discovery of penicillin in 1928 [5]. This breakthrough marked the beginning of a “golden age” of antibiotic discovery from the 1940s to the 1960s, during which most major antibiotic classes were identified [5]. Subsequent decades saw the development of synthetic and semisynthetic antibacterial drugs, while the discovery of fundamentally new antibiotic classes progressively declined [5]. More recently, the growing threat of antibiotic resistance has renewed global interest in antibacterial drugs with novel chemical scaffolds, targets, and mechanisms of action [2,3,6]. This renewed focus has contributed to the development of both approved and investigational antibacterial drugs with activity against priority pathogens and other clinically relevant antibiotic-resistant bacteria [2,3]. Recent approvals, emerging antibacterial candidates, and lessons from discontinued development programs, including barriers related to safety, efficacy, and emerging resistance, provide an opportunity to assess the progress and challenges of antibacterial development and inform future antibacterial design and clinical trials.

This review summarizes key antibacterial drugs that were in clinical development from 2010 to 2026 and were identified through searches of the PubMed database. The search was designed to identify antibacterial drugs evaluated in human Phase I-III clinical trials and was supplemented by targeted searches for individual antibacterials. The search strategy combined the major-topic Medical Subject Headings (MeSH) term “Anti-Bacterial Agents” or the title/abstract terms “antibiotic*” and “antibacterial*” with the MeSH term “Bacterial Infections.” These terms were combined with the MeSH term “Drug Development” or the title/abstract terms “investigational,” “development,” “pipeline,” “candidate,” and “first-in-human.” Clinical trials were identified using the publication types “Clinical Trial,” “Clinical Trial, Phase I,” “Clinical Trial, Phase II,” and “Clinical Trial, Phase III,” or the title/abstract terms “phase I,” “phase II,” and “phase III.” The search was restricted to human studies published from 1 January 2010, onward. Antibacterials were included regardless of their subsequent development or approval status and are organized into five major groups: (1) broad-spectrum, (2) Gram-positive infections, (3) Gram-negative infections, (4) mycobacterial infections, and (5) nontraditional treatments. The antibacterial classes, mechanisms of action, antibacterial spectrum, clinical applications, and development status of these antibacterials are highlighted, and associated resistance mechanisms and concerns are discussed. The antibacterial drugs covered in this review are summarized in Table 1, and representative chemical structures of Food and Drug Administration (FDA)-approved and emerging antibacterials with novel chemical scaffolds and distinct mechanisms of action are presented in Figure 1 and Figure 2, respectively. Vaccines, phage-based therapies, monoclonal antibodies, and microbiome-based interventions, including probiotics, live biotherapeutic products, and fecal microbiota transplantation, are beyond the scope of this review.

Table 1. Antibacterial drugs evaluated in clinical trials from 2010 to 2026: classes, mechanisms of action, clinical applications, and development status.

Antibacterial	Class/Mechanism of Action	Clinical Applications *	Development Status **	References
Broad-spectrum
Gepotidacin	Triazaacenaphthylene, inhibits DNA gyrase and topoisomerase IV and disrupts DNA replication	uUTIs, uncomplicated urogenital gonorrhea	FDA-approved	[7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]
Zoliflodacin	Spiropyrimidinetrione, primarily inhibits DNA gyrase and disrupts DNA replication	Uncomplicated urogenital gonorrhea	FDA-approved	[26,27,28,29,30,31,32]
Delafloxacin	Anionic fluoroquinolone, inhibits DNA gyrase and topoisomerase IV and disrupts DNA replication	ABSSSIs, CABP	FDA-approved	[33,34,35,36,37,38,39,40,41,42,43,44,45]
Ceftobiprole	Cephalosporin, binds PBPs and inhibits cell wall synthesis	ABSSSIs, bloodstream infections due to S. aureus (including right-sided infective endocarditis), CABP	FDA-approved	[46,47,48,49,50,51,52,53,54]
Ceftaroline	Cephalosporin, binds PBPs and inhibits cell wall synthesis	ABSSSIs, CABP	FDA-approved	[55,56,57,58,59,60,61,62,63,64,65,66]
GSK2251052	Oxaborole, inhibits leucyl-tRNA synthetase and protein synthesis	cUTIs studied	Development for cUTIs discontinued	[67,68,69,70,71,72,73,74,75]
GSK1322322	Hydrazinopyrimidine, inhibits peptide deformylase and disrupts protein maturation	CABP, ABSSSIs studied	Phase IIa completed, development discontinued	[76,77,78]
Plazomicin	Aminoglycoside, binds the 30S ribosomal subunit and inhibits protein synthesis	cUTIs, including acute pyelonephritis	FDA-approved	[79,80,81,82,83,84,85,86,87,88,89,90,91,92]
Lefamulin	Pleuromutilin, binds the 50S ribosomal subunit and inhibits protein synthesis	CABP, ABSSSIs studied	FDA-approved for CABP	[93,94,95,96,97]
Solithromycin	Fluoroketolide, binds the 50S ribosomal subunit and inhibits protein synthesis	CABP and uncomplicated urogenital gonorrhea studied	Phase III completed, FDA Complete Response Letter issued in 2016, not approved	[98,99,100,101,102,103,104,105,106,107,108,109,110,111,112]
NXL-103	Streptogramin combination, binds the 50S ribosomal subunit and inhibits protein synthesis	CABP, ABSSSIs studied	Phase II completed, subsequent development status unclear	[113,114,115,116]
Iclaprim	Diaminopyrimidine, inhibits dihydrofolate reductase and disrupts folate metabolism and DNA synthesis	ABSSSIs, nosocomial pneumonia studied	Phase III completed, development discontinued	[117,118,119,120,121,122,123,124,125]
NVC-422	Synthetic chloramine, oxidatively inactivates microbial components	Impetigo, ocular infections, and prevention of urinary catheter blockage studied	Phase IIb completed, subsequent development status unclear	[126,127,128,129,130]
LTX-109	Peptidomimetic, disrupts bacterial membrane and causes cell lysis	Topical skin infections, S. aureus nasal decolonization studied	Phase II completed	[131,132]
Rifasutenizol	Rifamycin-nitroimidazole conjugate, inhibits RNA synthesis and causes DNA damage	H. pylori infection, bacterial vaginosis studied	Phase III completed, application for approval under review in China	[133,134,135]
Gram-positive infections
Dalbavancin	Lipoglycopeptide, inhibits cell wall synthesis	ABSSSIs	FDA-approved	[136,137,138,139,140,141,142,143,144,145,146,147,148,149]
Oritavancin	Lipoglycopeptide, inhibits cell wall synthesis and disrupts bacterial membranes	ABSSSIs	FDA-approved	[150,151,152,153,154,155,156,157]
TD-1792	Glycopeptide-cephalosporin heterodimer, inhibits cell wall synthesis	cSSSIs studied	Phase III initiated, current status unclear	[158,159,160,161,162]
Tedizolid phosphate	Oxazolidinone, inhibits protein synthesis	ABSSSIs, HABP/VABP and bone and joint infections studied	FDA-approved for ABSSSIs	[163,164,165,166,167,168,169]
Cadazolid	Fluoroquinolone-oxazolidinone hybrid, primarily inhibits protein synthesis	C. difficile infection	Development discontinued	[170,171,172,173,174]
Fusidic acid	Steroidal antibiotic, inhibits protein synthesis	ABSSSIs and prosthetic joint infections investigated	Approved outside the United States, U.S. development inactive	[175,176,177,178,179]
CRS3123	Diaryldiamine, inhibits methionyl-tRNA synthetase and protein synthesis	C. difficile infection	Phase II completed	[180,181,182,183,184,185]
Ibezapolstat	Guanine derivative, inhibits DNA polymerase IIIC and DNA replication	C. difficile infection	Phase IIb completed, Phase III planned	[186,187,188,189,190,191]
DS-2969b	Imidazole-2-carboxamide, inhibits DNA gyrase subunit B and DNA replication	C. difficile infection	Development discontinued	[192,193,194]
Ridinilazole	Bis-benzimidazole, binds the DNA minor groove and disrupts transcription	C. difficile infection	Phase III completed, further clinical development planned	[195,196,197,198,199,200,201]
Fidaxomicin	Macrocyclic antibiotic, inhibits transcription	C. difficile-associated diarrhea	FDA-approved	[202,203,204,205,206,207,208,209,210,211,212,213,214,215,216]
Surotomycin	Cyclic lipopeptide, disrupts bacterial membranes	C. difficile infection	Development discontinued	[217,218,219,220,221,222,223,224,225]
XF-73	Dicationic porphyrin, disrupts bacterial membranes	S. aureus nasal decolonization	Phase II completed	[226,227,228,229,230]
Afabicin	Benzofuran-naphthyridinone, inhibits enoyl-acyl carrier protein reductase and fatty acid synthesis	ABSSSIs and bone and joint infections investigated	Phase II completed	[231,232,233,234]
DSTA4637S	Antibody-antibiotic conjugate, inhibits transcription	S. aureus bacteremia investigated	Phase Ib evaluated, current status unclear	[235,236]
α-Viniferin	Phytochemical with antistaphylococcal activity, precise target undetermined	S. aureus nasal decolonization investigated	Development status unclear	[237,238,239]
Gram-negative infections
HRS-8427	Siderophore cephalosporin, inhibits cell wall synthesis	cUTIs, HABP/VABP	Phase II/III	[240,241,242]
Cefiderocol	Siderophore cephalosporin, inhibits cell wall synthesis	cUTIs, HABP/VABP	FDA-approved	[243,244,245,246,247,248,249,250,251,252,253,254,255,256]
Benapenem	Carbapenem, inhibits cell wall synthesis	cUTIs, including acute pyelonephritis	Phase II/III	[257]
Cefepime-taniborbactam	Cephalosporin-β-lactamase inhibitor combination, inhibits cell wall synthesis and β-lactamases	cUTIs, including acute pyelonephritis	Phase III completed, FDA complete response letter issued	[258,259,260,261,262,263,264,265,266,267,268,269]
Ceftazidime-avibactam	Cephalosporin-β-lactamase inhibitor combination, inhibits cell wall synthesis and β-lactamases	cUTIs, cIAIs, HABP/VABP	FDA-approved	[270,271,272,273,274,275,276,277,278,279,280,281]
Ceftolozane-tazobactam	Cephalosporin-β-lactamase inhibitor combination, inhibits cell wall synthesis and β-lactamases	cUTIs, cIAIs, HABP/VABP	FDA-approved	[282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297,298]
Sulbactam-durlobactam	β-lactam-β-lactamase inhibitor combination, inhibits cell wall synthesis and β-lactamases	HABP/VABP caused by susceptible A. baumannii-calcoaceticus complex isolates	FDA-approved	[299,300,301,302,303,304]
Mycobacterial infections
Bedaquiline	Diarylquinoline, inhibits ATP synthase and depletes ATP	Pulmonary TB due to MDR M. tuberculosis (in combination therapy)	FDA-approved	[305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328,329,330,331,332]
Sudapyridine	Bedaquiline analog, inhibits ATP synthase and disrupts proton motive force	RR pulmonary TB due to M. tuberculosis studied	Phase III	[333,334,335,336,337,338,339,340,341]
Q203	Imidazopyridine amide, inhibits QcrB and cellular respiration	Drug-susceptible pulmonary TB due to M. tuberculosis studied, Buruli ulcer due to M. ulcerans studied	Phase II	[342,343,344,345,346]
BTZ-043	Benzothiazinone, inhibits DprE1 and cell wall arabinan synthesis	Drug-susceptible pulmonary TB due to M. tuberculosis studied	Phase IIb/c	[347,348,349,350,351,352,353,354]
PBTZ169	Benzothiazinone, inhibits DprE1 and cell wall arabinan synthesis	Drug-susceptible pulmonary TB due to M. tuberculosis studied	Phase II	[355,356,357]
Quabodepistat	Carbostyril, inhibits DprE1 and cell wall arabinan synthesis	Drug-susceptible and MDR pulmonary TB due to M. tuberculosis studied	Phase III ongoing	[358,359,360]
SQ109	Ethambutol-related diamine, inhibits MmpL3 and disrupts proton motive force	Drug-susceptible and MDR pulmonary TB due to M. tuberculosis studied	Phase IIb/III completed	[361,362,363,364,365,366]
Posizolid	Oxazolidinone, inhibits protein synthesis	Drug-susceptible pulmonary TB due to M. tuberculosis studied	Development discontinued	[367,368,369,370,371]
Contezolid	Oxazolidinone, inhibits protein synthesis	cSSTIs due to susceptible Gram-positive bacteria, pneumonia studied, pulmonary TB due to M. tuberculosis investigated	Approved in China for cSSTIs, TB use investigational	[372,373,374,375,376,377,378,379,380]
Sutezolid	Oxazolidinone, inhibits protein synthesis	Drug-susceptible pulmonary TB due to M. tuberculosis studied	Phase IIb/c	[381,382,383,384,385,386,387,388,389]
Pretomanid	Nitroimidazooxazine, inhibits cell wall synthesis and respiration	Drug-resistant pulmonary TB due to M. tuberculosis (in combination regimens)	FDA-approved	[316,326,390,391,392,393,394,395,396,397,398,399,400,401,402,403,404,405,406]
Delamanid	Nitroimidazooxazole, inhibits mycolic acid synthesis	MDR/RR-TB due to M. tuberculosis (in combination regimens)	Approved outside the U. S.	[401,405,407,408,409,410,411,412,413,414,415,416,417,418,419,420]
Nontraditional treatments
iOWH032	Host-directed oxadiazole-carboxamide, inhibits the cystic fibrosis transmembrane conductance regulator chloride channel and reduces intestinal chloride secretion	Cholera	Development discontinued	[421]
Ribaxamase	Recombinant β-lactamase, degrades β-lactam antibiotics released into the intestine to protect the gut microbiome	Prevention of C. difficile infection during intravenous β-lactam treatment	Phase IIb, development paused	[422,423,424]

* Clinical applications include approved indications and conditions evaluated in clinical studies. Conditions evaluated in clinical studies are not necessarily approved indications. ** Development status reflects publicly available information as of August 2026.

Figure 1. Representative chemical structures of FDA-approved antibacterials with novel chemical scaffolds and distinct mechanisms of action. Gepotidacin is a triazaacenaphthylene derivative that targets bacterial DNA gyrase and topoisomerase IV. Zoliflodacin is a spiropyrimidinetrione that primarily targets bacterial DNA gyrase, with weaker activity against topoisomerase IV. Bedaquiline is a diarylquinoline that targets the c- and ε-subunits of mycobacterial F₁F_O-ATP synthase, thereby inhibiting ATP synthesis and disrupting energy production. Pretomanid is a nitroimidazooxazine prodrug that, following activation, inhibits mycolic acid biosynthesis and disrupts mycobacterial respiration.

Figure 2. Representative chemical structures of emerging antibacterials with novel chemical scaffolds and distinct mechanisms of action. Ibezapolstat is a synthetic guanine derivative that targets DNA polymerase IIIC, thereby inhibiting DNA replication. CRS3123 is a diaryldiamine that targets bacterial methionyl-tRNA synthetase and inhibits protein synthesis. BTZ-043 is a benzothiazinone derivative that targets decaprenylphosphoryl-β-D-ribose 2’-epimerase 1, thereby inhibiting cell wall arabinan biosynthesis. Q203 is an imidazopyridine amide that targets the QcrB subunit of the cytochrome bcc-aa₃ oxidase of the mycobacterial electron transport chain.

2. Progress in Antibacterial Clinical Development Since 2010

2.1. Broad-Spectrum

Gepotidacin (GSK2140944, BLUJEPA). Gepotidacin is an FDA-approved, first-in-class, oral triazaacenaphthylene antibacterial with bactericidal activity against clinically important Gram-positive and Gram-negative pathogens (Figure 1). It inhibits bacterial DNA gyrase and topoisomerase IV through a unique binding mode that is distinct from fluoroquinolones, preventing cross-resistance. Specifically, it binds midway between the scissile DNA bonds and induces single-stranded DNA breaks to arrest the replication fork. This distinct mechanism allows it to retain activity against isolates carrying resistance determinants to established antibiotic classes, including multidrug-resistant (MDR) N. gonorrhoeae. Gepotidacin is FDA-approved for the treatment of uncomplicated urinary tract infections (uUTIs), including acute uncomplicated cystitis, caused by susceptible E. coli, K. pneumoniae, Citrobacter freundii complex, Staphylococcus saprophyticus, or Enterococcus faecalis. It is also FDA-approved for the treatment of uncomplicated urogenital gonorrhea. Clinical efficacy has been demonstrated in both uUTIs and uncomplicated urogenital gonorrhea, and gepotidacin has also been investigated for acute bacterial skin and skin structure infections (ABSSSIs). Its in vitro antibacterial spectrum includes pathogens such as E. coli, S. aureus, S. pneumoniae, and N. gonorrhoeae, as well as atypical bacteria such as Chlamydia trachomatis, Mycoplasma spp., and Ureaplasma spp. In vitro or preclinical activity has also been reported against selected anaerobic bacteria, Yersinia pestis, Bacillus anthracis, and drug-resistant mycobacteria, including nontuberculous mycobacteria (NTM) [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25].

Zoliflodacin (ETX0914, AZD0914, Nuzolvence). Zoliflodacin is an FDA-approved, first-in-class spiropyrimidinetrione antibacterial that primarily targets DNA gyrase, with weaker activity against topoisomerase IV, through a mechanism distinct from that of fluoroquinolones (Figure 1). It inhibits DNA replication by stabilizing cleaved gyrase-DNA complexes and preventing DNA religation. Consequently, it remains active against MDR N. gonorrhoeae, including isolates resistant to fluoroquinolones and other established antibiotic classes. It is FDA-approved as a single-dose oral treatment for uncomplicated urogenital gonorrhea caused by N. gonorrhoeae. Structurally, zoliflodacin contains an N-linked oxazolidinone substituent at the 3-position of the benzisoxazole ring fused to a spiropyrimidinetrione core. In vitro activity has also been reported against selected Gram-positive, fastidious Gram-negative, anaerobic, and atypical bacteria, including Chlamydia spp., Helicobacter pylori, Mycoplasma spp., and Ureaplasma spp. [26,27,28,29,30,31,32].

Delafloxacin (ABT-492, Baxdela). Delafloxacin is an FDA-approved, potent anionic fluoroquinolone with broad-spectrum activity against clinically important Gram-positive and Gram-negative bacteria, including certain drug-resistant isolates. Its antibacterial spectrum includes S. aureus, including methicillin-resistant S. aureus (MRSA), S. pneumoniae, E. faecalis, H. influenzae, Moraxella catarrhalis, Enterobacterales such as E. coli and K. pneumoniae, P. aeruginosa, Legionella spp., C. trachomatis, Chlamydia pneumoniae, Mycoplasma spp., and Ureaplasma spp. In vitro or preclinical activity has also been reported against selected anaerobic and microaerophilic bacteria, Y. pestis, N. gonorrhoeae, Neisseria meningitidis, H. pylori, Burkholderia pseudomallei, B. anthracis, Prevotella spp., Stenotrophomonas maltophilia, Clostridioides difficile, and selected NTM. Delafloxacin inhibits bacterial DNA gyrase and topoisomerase IV, thereby disrupting DNA replication, transcription, repair, and recombination. Its anionic character enhances bacterial uptake and antibacterial activity under acidic conditions, such as those encountered within inflamed tissues, abscesses, and biofilms, and in vitro antibiofilm activity has been demonstrated. It is FDA-approved for the treatment of ABSSSIs and community-acquired bacterial pneumonia (CABP), while its use for UTIs has also been clinically evaluated [33,34,35,36,37,38,39,40,41,42,43,44,45].

Ceftobiprole (Ro 63-9141, BAL9141, Zevtera, Mabelio, ceftobiprole medocaril sodium). Ceftobiprole is an FDA-approved, broad-spectrum cephalosporin of the pyrrolidinone-3-ylidenemethyl cephem class with bactericidal activity against a wide range of Gram-positive and Gram-negative aerobic bacteria, particularly MRSA, but it has limited activity against many anaerobes. Ceftobiprole inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs), including PBP2a in MRSA and PBP2x in penicillin-resistant pneumococci. Its antibacterial spectrum includes drug-resistant staphylococci and streptococci, as well as susceptible E. faecalis, H. influenzae, M. catarrhalis, E. coli, P. aeruginosa, Enterobacter cloacae, and K. pneumoniae. In vitro or preclinical activity has also been reported against selected isolates of A. baumannii, B. pseudomallei, N. gonorrhoeae, and Francisella tularensis. Its FDA-approved indications include ABSSSIs, S. aureus bloodstream infections (bacteremia), including cases with right-sided infective endocarditis, and CABP. Ceftobiprole has also been evaluated for hospital-acquired bacterial pneumonia (HABP) and bone and joint infections, but these are not FDA-approved indications [46,47,48,49,50,51,52,53,54].

Ceftaroline (TAK-599, PPI-0903, Teflaro, ceftaroline fosamil). Ceftaroline is an FDA-approved, broad-spectrum cephalosporin with bactericidal activity against MDR Gram-positive and selected Gram-negative pathogens. It inhibits bacterial cell wall synthesis by binding to PBPs, exhibiting high affinity for PBP2a in MRSA and PBP2x in penicillin-resistant S. pneumoniae. Its antibacterial spectrum includes S. aureus, including MRSA, S. pneumoniae, H. influenzae, M. catarrhalis, and susceptible Enterobacterales such as E. coli and K. pneumoniae. In vitro activity has also been demonstrated against vancomycin-susceptible E. faecalis and selected Gram-positive anaerobes, although the clinical significance of this activity is less well established. Ceftaroline also exhibits in vitro activity against established S. aureus biofilms and has been reported to have a relatively limited impact on the human intestinal microbiota. Its FDA-approved indications are ABSSSIs, including cases with concurrent S. aureus bacteremia, and CABP, including cases with concurrent S. pneumoniae bacteremia, in both adult and pediatric patients. Off-label or investigational applications include severe MRSA infections such as primary bloodstream infections, infective endocarditis, osteomyelitis and other bone and joint infections, prosthetic joint infections, and meningitis. It has also been evaluated in diabetic foot, postoperative surgical-site, and other complicated wound infections. Mutations in PBP2a and alterations in or increased expression of PBP4 can confer reduced susceptibility or resistance to this antibacterial in S. aureus [55,56,57,58,59,60,61,62,63,64,65,66].

GSK2251052 (Epetraborole, AN3365). GSK2251052 is an investigational, broad-spectrum, benzoxaborole-class boron-containing leucyl-tRNA synthetase (LeuRS) inhibitor with activity against MDR Gram-negative bacteria, including carbapenem-resistant strains of E. coli, K. pneumoniae, and P. aeruginosa. It inhibits bacterial protein synthesis through an oxaborole tRNA-trapping mechanism that captures the terminal adenosine of tRNA^Leu within the LeuRS editing site. Its in vitro antibacterial spectrum also includes anaerobic bacteria, including Bacteroides fragilis, Bacteroides thetaiotaomicron, and Clostridium perfringens, as well as B. pseudomallei, N. gonorrhoeae, and C. trachomatis. Resistance to GSK2251052 emerged rapidly during a Phase II clinical trial for complicated UTIs (cUTIs) owing to mutations in the editing domain of LeuRS, leading to the discontinuation of its original development program for Gram-negative infections. DS86760016 is a newer preclinical LeuRS inhibitor with an improved pharmacokinetic profile and a lower frequency of resistance development than GSK2251052 in animal infection models. Both GSK2251052 and DS86760016 exhibit in vitro, intracellular, and preclinical in vivo activity against Mycobacterium abscessus, and DS86760016 also exhibits in vitro activity against other NTM species [67,68,69,70,71,72,73,74,75].

GSK1322322 (Lanopepden). GSK1322322 is an investigational hydroxamic acid-class inhibitor of bacterial peptide deformylase (PDF), an essential enzyme that removes the formyl group from newly synthesized bacterial proteins. Inhibition of PDF disrupts protein maturation and provides activity against MDR respiratory and skin pathogens, including S. aureus, S. pneumoniae, Streptococcus pyogenes, H. influenzae, and M. catarrhalis. It has been clinically evaluated for CABP and ABSSSIs. Further development by GSK was discontinued after potentially reactive metabolites were identified in nonclinical studies, raising concern about possible toxicity that outweighed the anticipated benefit in community-acquired infections [76,77,78].

Plazomicin (ACHN-90, ACHN-490, Zemdri). Plazomicin is an FDA-approved, semisynthetic, next-generation aminoglycoside derived from sisomicin that binds to the 16S rRNA decoding site of the bacterial 30S ribosomal subunit, disrupting translation and inhibiting protein synthesis. Its antibacterial spectrum includes MDR Gram-negative bacilli and selected Gram-positive cocci, particularly Enterobacterales, including isolates of E. coli, K. pneumoniae, and Enterobacter spp. that produce extended-spectrum β-lactamases (ESBLs), AmpC-β-lactamases, or carbapenemases, as well as Proteus mirabilis. In vitro activity has also been reported against selected isolates of P. aeruginosa, A. baumannii, MRSA, and colistin-resistant Gram-negative bacteria, although activity against P. aeruginosa and A. baumannii is variable. In vitro or preclinical activity has also been demonstrated against Brucella spp. and Y. pestis. Plazomicin is FDA-approved for the treatment of cUTIs, including acute pyelonephritis, caused by susceptible E. coli, K. pneumoniae, P. mirabilis, and E. cloacae, in patients with limited or no alternative treatment options. Acquired 16S rRNA methyltransferases confer resistance to plazomicin by modifying its ribosomal target. In addition, the recently identified gentamicin-resistance gene grdA has been reported to confer high-level plazomicin resistance in Salmonella enterica, although its precise biochemical mechanism remains to be determined [79,80,81,82,83,84,85,86,87,88,89,90,91,92].

Lefamulin (BC-3781, Xenleta, lefamulin acetate). Lefamulin is an FDA-approved, semisynthetic pleuromutilin and the first member of this class approved for systemic use in humans. It inhibits bacterial protein synthesis by binding to the peptidyl transferase center of the 50S ribosomal subunit. Lefamulin is active against clinically important respiratory pathogens, including S. aureus, including MRSA, S. pneumoniae, H. influenzae, and M. catarrhalis, Legionella pneumophila, Mycoplasma pneumoniae, and C. pneumoniae. In vitro activity has also been demonstrated against sexually transmitted pathogens, including Mycoplasma genitalium, C. trachomatis, and N. gonorrhoeae. Its FDA-approved indication is the treatment of CABP, while it has also been clinically evaluated for ABSSSIs [93,94,95,96,97].

Solithromycin (CEM-101, OP-1068, Solithera). Solithromycin is an investigational fluoroketolide that binds to the bacterial 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis. Its in vitro antibacterial spectrum primarily includes Gram-positive bacteria and selected fastidious Gram-negative and atypical pathogens, particularly respiratory tract pathogens, including S. aureus, S. pneumoniae, Streptococcus agalactiae, S. pyogenes, Enterococcus spp., H. influenzae, M. catarrhalis, Listeria monocytogenes, L. pneumophila, and Bordetella pertussis, as well as C. trachomatis, C. pneumoniae, N. meningitidis, N. gonorrhoeae, Mycoplasma spp., and Ureaplasma spp. It has been clinically evaluated for CABP and uncomplicated urogenital gonorrhea. Although Phase III trials demonstrated noninferiority to moxifloxacin in CABP, solithromycin has not received FDA approval. In a 2016 Complete Response Letter, the FDA requested additional data to characterize the risk of hepatic toxicity and resolution of manufacturing deficiencies [98,99,100,101,102,103,104,105,106,107,108,109,110,111,112].

NXL-103 (XRP 2868). NXL-103 is an investigational, orally administered, semisynthetic combination of the streptogramins linopristin and flopristin, which act at distinct sites on the bacterial 50S ribosomal subunit. Linopristin blocks peptide-chain elongation, whereas flopristin inhibits the peptidyl transferase center. Together, they inhibit bacterial protein synthesis. Its in vitro antibacterial spectrum primarily includes Gram-positive bacteria, including S. aureus, including MRSA, S. pneumoniae, S. pyogenes, Enterococcus spp., and Gram-positive anaerobes, as well as selected respiratory Gram-negative bacteria, including Haemophilus spp. and M. catarrhalis. It was clinically evaluated in Phase II trials for CABP and ABSSSIs but has not received regulatory approval [113,114,115,116].

Iclaprim (RO-48-2622, AR-100). Iclaprim is an investigational diaminopyrimidine that selectively inhibits bacterial dihydrofolate reductase, thereby disrupting folate metabolism and DNA synthesis. It is active against drug-resistant Gram-positive pathogens, including S. aureus, including MRSA, S. pneumoniae, S. pyogenes, and S. agalactiae. In vitro activity has also been reported against selected Gram-negative and atypical bacteria, including C. trachomatis, C. pneumoniae, N. gonorrhoeae, L. pneumophila, as well as the Gram-positive pathogen L. monocytogenes. It reached Phase III evaluation for ABSSSIs and was also evaluated for nosocomial pneumonia, but it did not receive FDA approval. A 2009 Complete Response Letter requested additional evidence of efficacy, and a 2019 letter requested additional data on the risk of hepatic toxicity. Its development was subsequently discontinued. At subinhibitory concentrations, iclaprim has also been shown in vitro to suppress the production of selected S. aureus exotoxins [117,118,119,120,121,122,123,124,125].

NVC-422 (N,N-dichloro-2,2-dimethyltaurine, Auriclosene). NVC-422 is an investigational, broad-spectrum synthetic chloramine and stable analog of N-chlorotaurine that inactivates bacterial proteins through oxidation and has rapid microbicidal activity against Gram-positive and Gram-negative bacteria, including E. coli, P. aeruginosa, Staphylococcus spp., and Enterococcus spp. It reached Phase IIb clinical evaluation in topical formulations for impetigo and ocular infections and Phase II evaluation as an irrigant for preventing urinary catheter blockage and encrustation. It also exhibits in vitro antibiofilm activity, and serial-passage studies indicate a low propensity for resistance development. In addition to its direct microbicidal activity, NVC-422 has also been shown in vitro to inactivate virulence factors produced by S. aureus and E. coli. However, it has not received regulatory approval [126,127,128,129,130].

LTX-109 (Voxvoganan, Lytixar). LTX-109 is an investigational, broad-spectrum, rapidly acting synthetic antimicrobial peptidomimetic intended for topical use. It exhibits rapid bactericidal activity against Staphylococcus spp., including MRSA and isolates resistant to several other antibiotic classes. It binds to negatively charged components of bacterial membranes, causing membrane disruption and cell lysis. Serial-passage studies indicate a low propensity for resistance development. It has been clinically evaluated for the topical treatment of Gram-positive skin infections and nasal decolonization of methicillin-susceptible S. aureus (MSSA) and MRSA but has not received regulatory approval [131,132].

Rifasutenizol (TNP-2198). Rifasutenizol is an investigational, stable covalent conjugate of rifamycin and nitroimidazole pharmacophores designed as a dual-targeting antibacterial for microaerophilic and anaerobic infections. The rifamycin moiety inhibits bacterial DNA-dependent RNA polymerase, whereas reductive activation of the nitroimidazole moiety generates reactive intermediates that damage bacterial DNA. It exhibits activity against selected microaerophilic and anaerobic pathogens, including H. pylori, C. difficile, and Gardnerella vaginalis. Clinical development has included bacterial vaginosis but has focused primarily on H. pylori infection, for which Phase III evaluation has been completed and an application for approval is under review in China [133,134,135].

Collectively, these broad-spectrum antibacterials demonstrate that recent antibacterial development has involved both improvements to established antibiotic classes and the discovery of new chemical scaffolds, targets, and mechanisms of action (Table 1). The successful development of gepotidacin and zoliflodacin, which target bacterial topoisomerases through mechanisms distinct from those of fluoroquinolones, together with delafloxacin, ceftobiprole, ceftaroline, plazomicin, and lefamulin, which build on established classes, illustrates the potential of both approaches. In contrast, the discontinuation of several candidates, including GSK1322322 following safety concerns and GSK2251052 following the emergence of resistance during treatment, underscores the challenges of translating promising antibacterial activity into clinical success and highlights the need to assess safety and resistance potential early in development.

2.2. Gram-Positive Infections

Dalbavancin (BI 397, BI 387, Dalvance). Dalbavancin is an FDA-approved, semisynthetic, long-acting lipoglycopeptide that binds the D-Ala-D-Ala terminus of peptidoglycan precursors and inhibits bacterial cell wall synthesis. It is active against Gram-positive pathogens, including MRSA, other susceptible staphylococci, streptococci, vancomycin-susceptible E. faecalis, and some Gram-positive anaerobes. It is approved for the treatment of ABSSSIs in adult and pediatric patients. Its off-label use and investigation have included bloodstream infections, including catheter-related infections, bone and joint infections, including osteomyelitis and prosthetic joint infections, diabetic foot infections, endocarditis, device-associated infections, and surgical-site infections. Dalbavancin has shown activity against staphylococcal biofilms and has been shown to reduce S. aureus exotoxin production in vitro. A small study in healthy volunteers found limited effects on intestinal microbiota. In vitro activity has also been reported against B. anthracis, C. difficile, Corynebacterium spp., L. monocytogenes, and Micrococcus spp. Reduced susceptibility has emerged during treatment, with walK mutations identified in some resistant staphylococcal isolates [136,137,138,139,140,141,142,143,144,145,146,147,148,149].

Oritavancin (LY333328, Orbactiv, Kimysra). Oritavancin is an FDA-approved, semisynthetic, long-acting lipoglycopeptide that binds D-Ala-D-Ala terminus of cell wall precursor lipid II to inhibit peptidoglycan synthesis and disrupts bacterial membrane integrity. It is active against drug-resistant Gram-positive bacteria, including MRSA, other susceptible staphylococci, streptococci, and vancomycin-susceptible E. faecalis. In vitro activity has also been reported against C. difficile, B. anthracis, vancomycin-resistant enterococci (VRE), and some Gram-positive anaerobes. It is approved for the treatment of ABSSSIs in adults. Its off-label use and investigation have included bloodstream infections, including catheter-related infections, infective endocarditis, surgical-site infections, pneumonia, and bone and joint infections, including osteomyelitis and prosthetic joint infections [150,151,152,153,154,155,156,157].

TD-1792 (Cefilavancin). TD-1792 is an investigational, first-in-class, multivalent glycopeptide-cephalosporin heterodimer whose components are proposed to bind peptidoglycan precursors and PBPs, respectively, with potent activity against Gram-positive bacteria, including MRSA. In vitro activity has also been reported against anaerobic Gram-positive bacteria and Corynebacterium spp. Following evaluation for complicated skin and skin structure infections (cSSSIs) in a Phase II trial, its clinical evaluation advanced into Phase III trials, although its subsequent development status is unclear [158,159,160,161,162].

Tedizolid phosphate (TR-701, DA-7218, Sivextro). Tedizolid phosphate is an FDA-approved, second-generation oxazolidinone prodrug whose active moiety, tedizolid (DA-7157, torezolid, TR-700), binds to the peptidyl transferase center of the bacterial 50S ribosomal subunit and inhibits protein synthesis. Tedizolid is active against Gram-positive pathogens, including MSSA, MRSA, isolates of S. pneumoniae that are penicillin-susceptible, penicillin-resistant, or MDR, and susceptible enterococci. In vitro activity has also been demonstrated against VRE, certain linezolid-resistant staphylococci and enterococci, M. tuberculosis, some NTM, Nocardia brasiliensis, and the anaerobe B. fragilis. Tedizolid phosphate is approved for the treatment of ABSSSIs in adult and pediatric patients. It has also been evaluated in a Phase III trial for HABP/ventilator-associated bacterial pneumonia (VABP) and investigated for bone and joint infections [163,164,165,166,167,168,169].

Cadazolid. Cadazolid is an investigational, narrow-spectrum, bactericidal fluoroquinolone-oxazolidinone hybrid developed for the treatment of C. difficile infection. It primarily inhibits bacterial protein synthesis by binding near the peptidyl transferase center of the ribosome and has weaker inhibitory effects on DNA synthesis, with a low potential for spontaneous resistance development observed in vitro. Its antibacterial spectrum includes epidemic C. difficile strains and isolates resistant to linezolid or moxifloxacin, and it also inhibits toxin production and spore formation in vitro. It is minimally absorbed and has shown a limited impact on the gut microflora in experimental models. In Phase III trials, cadazolid did not meet the clinical-cure noninferiority endpoint in one of two studies, and its development was discontinued [170,171,172,173,174].

Fusidic acid (CEM-102). Fusidic acid is a long-used steroidal antistaphylococcal antibacterial active against staphylococci, including MRSA. It inhibits bacterial protein synthesis through interaction with elongation factor G. In vitro activity has also been demonstrated against N. gonorrhoeae and C. trachomatis. It has been clinically investigated for ABSSSIs in a Phase III trial and for prosthetic joint infections in a Phase II combination trial with rifampicin that was prematurely terminated because of a drug–drug interaction [175,176,177,178,179].

CRS3123 (REP3123). CRS3123 is a novel diaryldiamine that targets bacterial methionyl-tRNA synthetase and inhibits protein synthesis in Gram-positive bacteria (Figure 2). It is highly active against C. difficile, including resistant strains, and aerobic Gram-positive cocci, but has limited activity against many commensal intestinal anaerobes and most Gram-negative bacteria. It also inhibits spore and toxin production in experimental studies, and its narrow spectrum is associated with limited disruption of the normal gut microbiota. In a small Phase II trial for C. difficile infection, CRS3123 showed clinical activity and numerically lower recurrence rates than vancomycin [180,181,182,183,184,185].

Ibezapolstat (ACX-362E, MorE-DCBG). Ibezapolstat is a synthetic guanine derivative, N²-(3,4-dichlorobenzyl)-7-(2-[1-morpholinyl]ethyl)guanine, and a first-in-class DNA polymerase IIIC inhibitor that inhibits DNA replication in C. difficile (Figure 2). As a Gram-positive-selective antibacterial, it has shown more favorable effects on gut microbiome composition compared with vancomycin, including the preservation or regrowth of certain commensal bacteria. It has also shown clinical activity against C. difficile infection in Phase IIa and IIb studies, with preliminary findings suggesting a lower risk of recurrence, and exhibits in vitro activity against MDR strains, with Phase III evaluation planned [186,187,188,189,190,191].

DS-2969b. DS-2969b is a novel DNA gyrase subunit B inhibitor that blocks the supercoiling activity of C. difficile DNA gyrase and inhibits DNA replication. Oral DS-2969b was evaluated in Phase I studies in healthy volunteers as a potential treatment for C. difficile infection, though further clinical development has since been discontinued for reasons that have not been publicly reported. Its intravenous prodrug, DS11960558, was evaluated in preclinical studies. In vitro activity has also been demonstrated against Gram-positive aerobes, including MRSA [192,193,194].

Ridinilazole (SMT19969). Ridinilazole is a novel, narrow-spectrum, nonabsorbable bis-benzimidazole with potent activity against C. difficile but limited activity against many other Gram-positive and Gram-negative aerobic and anaerobic intestinal bacteria. It binds to the DNA minor groove, resulting in transcriptional dysregulation and bacterial cell death. Experimental studies have also shown impaired cell division and reduced toxin production. It has demonstrated clinical activity against C. difficile infection while preserving gut microbiome diversity better than vancomycin. In a Phase III trial, recurrence was lower with ridinilazole, although it did not meet the primary endpoint for superiority in sustained clinical response. Further clinical development is planned [195,196,197,198,199,200,201].

Fidaxomicin (OPT-80, PAR-101, Difimicin, Lipiarmycin A3, Dificid, Tiacumicin B, Clostomicin B1). Fidaxomicin is a narrow-spectrum, FDA-approved, macrocyclic antibiotic that binds to bacterial RNA polymerase and inhibits transcription. Its antibacterial activity is primarily directed against the Gram-positive pathogen C. difficile, with little or no activity against Gram-negative bacteria such as Bacteroides spp. It is approved for the treatment of C. difficile-associated diarrhea in adult and pediatric patients. It largely preserves the normal gut microbiota compared with vancomycin, helping maintain microbiome diversity and colonization resistance. It also inhibits sporulation and toxin production and shows activity against established C. difficile biofilms in experimental studies. Clinical trials have found lower recurrence rates with fidaxomicin than with standard vancomycin treatment. Mutations in rpoB or rpoC, which encode the β and β’ subunits, respectively, of bacterial RNA polymerase, can reduce susceptibility to fidaxomicin [202,203,204,205,206,207,208,209,210,211,212,213,214,215,216].

Surotomycin (CB-183,315, MK-4261). Surotomycin is an investigational, membrane-active, bactericidal cyclic lipopeptide that disrupts bacterial membrane potential, with potent activity against C. difficile, including antibiotic-resistant strains. It is a structural analog of daptomycin and was evaluated for C. difficile infection in two Phase III trials, meeting the noninferiority criterion against vancomycin in one trial but not the other. Due to these discordant results, its development has been discontinued. Its in vitro antibacterial spectrum also includes a broad range of Gram-positive aerobic and anaerobic pathogens, including MRSA and vancomycin-susceptible and vancomycin-resistant strains of E. faecalis and Enterococcus faecium. It exhibits a low frequency of resistance development in vitro and has been shown to reduce toxin production under some experimental conditions. Its limited activity against Gram-negative anaerobes and Enterobacteriaceae spares some components of the gut microbiota, although effects on Gram-positive intestinal bacteria have been observed [217,218,219,220,221,222,223,224,225].

XF-73 (Exeporfinium chloride). XF-73 is an investigational, first-in-class, dicationic porphyrin derivative that disrupts bacterial membrane integrity and has rapid bactericidal activity against staphylococci. Its in vitro antibacterial spectrum includes antibiotic-susceptible and antibiotic-resistant Gram-positive bacteria. A Phase II clinical study found that XF-73 reduced S. aureus nasal carriage. It is also active against slow-growing, non-dividing, and biofilm-associated S. aureus cells in vitro [226,227,228,229,230].

Afabicin (Debio 1450, AFN-1720). Afabicin is a novel, first-in-class, narrow-spectrum antistaphylococcal antibacterial under development. As a prodrug, afabicin is converted in vivo to its active form, afabicin desphosphono (Debio 1452, AFN-1252), which inhibits enoyl-acyl carrier protein reductase, an enzyme critical for fatty acid biosynthesis in staphylococci. Its antibacterial spectrum is primarily restricted to S. aureus, including MSSA and MRSA, as well as coagulase-negative staphylococci, with limited activity against other Gram-positive or Gram-negative species. It has been clinically evaluated in Phase II trials for ABSSSIs and bone and joint infections. Oral afabicin has shown limited disruption of the gut microbiota in healthy volunteers [231,232,233,234].

DSTA4637S (RG7861). DSTA4637S is a novel antibody-antibiotic conjugate designed to eliminate S. aureus within host cells, where it can evade standard-of-care antibiotics. The conjugate consists of an anti-S. aureus Thiomab human immunoglobulin G1 monoclonal antibody linked to a novel rifamycin-class antibiotic, 4-dimethylaminopiperidino-hydroxybenzoxazino rifamycin (dmDNA31), through a protease-cleavable linker. The antibody binds S. aureus, and following uptake into host cells, intracellular proteases cleave the linker to release dmDNA31, which inhibits bacterial RNA polymerase. DSTA4637S has been evaluated in a Phase I study in healthy volunteers and a Phase Ib study in patients with S. aureus bacteremia receiving standard-of-care antibiotics [235,236].

α-Viniferin. α-Viniferin is a bioactive phytochemical compound with in vitro activity against drug-susceptible and drug-resistant strains of M. tuberculosis and staphylococci, including MSSA, MRSA, and methicillin-resistant Staphylococcus epidermidis. In a small clinical study, topical α-viniferin reduced nasal S. aureus carriage without significantly reducing the other nasal bacteria measured. Its precise antibacterial target has not been established [237,238,239].

Overall, the development of Gram-positive antibacterials demonstrates the continued advancement of established antibiotic classes alongside a growing emphasis on narrow-spectrum antibacterials with novel targets and mechanisms of action (Table 1). The successful development of dalbavancin, oritavancin, tedizolid, and fidaxomicin, together with the investigation of CRS3123, ibezapolstat, and afabicin, illustrates the potential of both established and targeted approaches against Gram-positive pathogens. In particular, narrow-spectrum antibacterials directed against C. difficile and S. aureus reflect increasing interest in pathogen-selective activity with the potential to limit disruption of the normal microbiota. Other approaches, including membrane-active antibacterials and an antibody-antibiotic conjugate designed to reach intracellular S. aureus, broaden the strategies being explored. However, mixed outcomes in late-stage trials for several candidates underscore the need to establish clear clinical benefits alongside antibacterial activity.

2.3. Gram-Negative Infections

HRS-8427. HRS-8427 is a novel parenteral siderophore cephalosporin currently in Phase II/III clinical development for the treatment of aerobic Gram-negative bacterial infections, including cUTIs and HABP/VABP. It exploits bacterial iron-uptake systems to enter the periplasm, where it binds PBPs and inhibits cell wall biosynthesis. HRS-8427 has demonstrated potent in vitro activity against MDR Gram-negative bacteria, including carbapenem-resistant Enterobacterales (CRE), P. aeruginosa, and A. baumannii, as well as favorable pharmacokinetic and safety profiles in early clinical studies [240,241,242].

Cefiderocol (S-649266, Fetroja). Cefiderocol is an FDA-approved siderophore cephalosporin that forms a ferric iron-chelating complex, exploiting bacterial iron transport systems to enter the periplasm of Gram-negative bacteria. After entry, it binds primarily to PBP3 and inhibits peptidoglycan synthesis. Cefiderocol exhibits potent in vitro activity against MDR Gram-negative pathogens, including ESBL-producing, carbapenemase-producing, and carbapenem-resistant isolates of E. coli, K. pneumoniae, Enterobacter spp., P. aeruginosa, A. baumannii, S. maltophilia, the Burkholderia cepacia complex, B. pseudomallei, and Achromobacter spp., including isolates harboring diverse serine β-lactamases and metallo-β-lactamases. FDA-approved indications include cUTIs, including acute pyelonephritis, and HABP/VABP in adults with infections caused by susceptible Gram-negative bacteria. Cefiderocol has also been evaluated for complicated intra-abdominal infections (cIAIs) and bloodstream infections, while its use for osteomyelitis, prosthetic joint infections, meningitis, endocarditis, and ventriculitis has been described primarily in case reports and observational studies. It also exhibits in vitro activity against biofilm-associated Gram-negative bacteria. Resistance can result from β-lactamase production, mutations affecting PBPs, and alterations in TonB-dependent siderophore receptors, including PiuA, CirA, and FptA in different bacterial species, that reduce drug uptake [243,244,245,246,247,248,249,250,251,252,253,254,255,256].

Benapenem. Benapenem is a novel investigational intravenous carbapenem with potent in vitro activity against Enterobacterales, including ESBL-producing E. coli, K. pneumoniae, and E. cloacae isolates. It binds PBPs and inhibits bacterial cell wall synthesis. Benapenem has a prolonged elimination half-life that supports once-daily administration and has been evaluated in a combined Phase II/III clinical trial for cUTIs, including acute pyelonephritis [257].

Cefepime-taniborbactam. Cefepime-taniborbactam is an investigational broad-spectrum antibacterial combination consisting of the fourth-generation cephalosporin cefepime and the novel bicyclic boronate β-lactamase inhibitor taniborbactam. It exhibits potent in vitro activity against MDR Gram-negative bacteria, including ESBL-producing strains, CRE, and MDR P. aeruginosa isolates. Activity has also been reported against selected isolates of S. maltophilia, the B. cepacia complex, and B. pseudomallei. Mechanistically, cefepime binds PBPs and inhibits cell wall synthesis, whereas taniborbactam inhibits serine-β-lactamases from Ambler classes A, C, and D, as well as several class B metallo-β-lactamases, including many NDM- and VIM-type enzymes, thereby protecting cefepime from hydrolysis. It also inhibits cefepime-hydrolyzing PDC variants, including PDC-88, thereby restoring cefepime activity. However, resistance has been associated with IMP-type enzymes and certain NDM and VIM variants, including NDM-9. Clinically, this combination demonstrated superiority over meropenem in a Phase III clinical trial for cUTIs, including acute pyelonephritis. Although the FDA issued a Complete Response Letter requesting additional chemistry, manufacturing, and controls information, it identified no deficiencies related to clinical safety or efficacy, and development remains ongoing [258,259,260,261,262,263,264,265,266,267,268,269].

Ceftazidime-avibactam (Avycaz). Ceftazidime-avibactam is an FDA-approved antibacterial combination consisting of ceftazidime, a cephalosporin that binds PBPs and inhibits cell wall synthesis, and avibactam, a non-β-lactam β-lactamase inhibitor (formerly designated AVE1330A and NXL104). Avibactam belongs to the diazabicyclooctane class and inhibits Ambler classes A and C β-lactamases and certain class D β-lactamases, including KPC and OXA-48-like carbapenemases, but lacks activity against class B metallo-β-lactamases. This combination is active against MDR Gram-negative pathogens, particularly Enterobacterales, such as E. coli and K. pneumoniae, including ESBL- and serine-carbapenemase-producing strains. Clinically relevant activity has also been demonstrated against P. aeruginosa and selected isolates of the B. cepacia complex. Approved clinical indications include cUTIs, including acute pyelonephritis, cIAIs, when administered in combination with metronidazole, and HABP/VABP. Off-label clinical use has also been documented for bloodstream infections, bone and joint infections, endocarditis, and central nervous system (CNS) infections caused by susceptible Gram-negative bacteria. However, emerging resistance poses a clinical challenge. Mutations and structural alterations in KPC enzymes, particularly substitutions or deletions within the Ω-loop, such as the D179Y substitution, can emerge following treatment and can confer resistance to ceftazidime-avibactam. Altered membrane permeability, upregulated efflux pumps, and increased expression or structural modification of other β-lactamases contribute to treatment failure [270,271,272,273,274,275,276,277,278,279,280,281].

Ceftolozane-tazobactam (Zerbaxa). Ceftolozane-tazobactam is an FDA-approved antibacterial combination consisting of ceftolozane, an oxyimino-aminothiazolyl cephalosporin that binds PBPs, particularly PBP3, to inhibit cell wall synthesis, and tazobactam, a β-lactamase inhibitor that protects ceftolozane from hydrolysis by susceptible β-lactamases. The combination has potent antipseudomonal activity against MDR and selected extensively drug-resistant (XDR) P. aeruginosa isolates. Its antibacterial spectrum includes P. aeruginosa, with in vitro activity against biofilm-associated bacteria and isolates recovered from patients with cystic fibrosis, as well as Enterobacterales such as E. coli, K. pneumoniae, and E. cloacae complex isolates, including many ESBL-producing isolates. Variable in vitro activity has also been reported against selected isolates of the B. cepacia complex, B. pseudomallei, H. influenzae, and Salmonella spp., with good activity against many B. fragilis isolates but variable or limited activity against other Bacteroides species. Approved indications in adult and pediatric patients include cUTIs, including pyelonephritis, cIAIs, when administered in combination with metronidazole, and HABP/VABP. Reported off-label uses included bloodstream infections, including those associated with sepsis, pulmonary infections outside the approved HABP/VABP protocol, bone and joint infections, including osteomyelitis, CNS infections, including meningitis, endocarditis, and otitis. Resistance is associated with the overexpression or structural modification of PDC, ampD mutations that promote PDC derepression, OXA-2 variants carrying a D149 duplication, such as OXA-539, the acquisition of horizontally transferred metallo-β-lactamases, OXA-type β-lactamases, and VEB β-lactamases, as well as mutations that promote the overexpression of the MexCD-OprJ efflux pump [282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297,298].

Sulbactam-durlobactam (Xacduro). Sulbactam-durlobactam is an FDA-approved antibacterial combination consisting of sulbactam and durlobactam (formerly designated ETX2514), a novel broad-spectrum diazabicyclooctane serine β-lactamase inhibitor. Sulbactam exerts intrinsic antibacterial activity against the A. baumannii-calcoaceticus complex by binding PBPs and inhibiting cell wall synthesis, whereas durlobactam inhibits class A, C, and D β-lactamases that would otherwise hydrolyze sulbactam. This combination is active against MDR and carbapenem-resistant isolates of the A. baumannii-calcoaceticus complex. Its FDA-approved indication is the treatment of HABP/VABP caused by susceptible isolates of this complex in adults with limited or no alternative treatment options. Preclinical activity has also been demonstrated against pathogenic Burkholderia species [299,300,301,302,303,304].

Together, the development of Gram-negative antibacterials has focused on complementary strategies, including combinations of β-lactams and β-lactamase inhibitors that counter diverse serine β-lactamases and, in some cases, metallo-β-lactamases, siderophore cephalosporins that exploit bacterial iron-uptake systems to overcome outer-membrane permeability barriers, pathogen-directed combinations such as sulbactam-durlobactam, and a carbapenem with improved pharmacokinetic properties (Table 1). The FDA approvals of cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam, and sulbactam-durlobactam, together with the clinical development of HRS-8427, cefepime-taniborbactam, and benapenem, support the potential of these approaches to expand treatment options for infections caused by MDR Gram-negative pathogens. However, resistance mediated by β-lactamase acquisition or modification, altered PBPs, reduced siderophore-mediated uptake, decreased membrane permeability, and increased efflux emphasizes the continued need to anticipate and monitor resistance during antibacterial development and clinical use.

2.4. Mycobacterial Infections

Bedaquiline (R207910, TMC207, Sirturo). Bedaquiline is a first-in-class, FDA-approved diarylquinoline with potent bactericidal activity (Figure 1). While it possesses in vitro activity against drug-susceptible and drug-resistant strains of M. tuberculosis, it is FDA-approved as part of combination therapy for pulmonary tuberculosis (TB) caused by M. tuberculosis resistant to at least rifampicin and isoniazid. It also exhibits in vitro antimycobacterial activity against other mycobacterial species, including Mycobacterium leprae, Mycobacterium ulcerans, and members of the Mycobacterium avium, M. abscessus, and Mycobacterium fortuitum complexes. Bedaquiline interacts with the c-ring and ε-subunit of mycobacterial F₁F_O-ATP synthase, thereby inhibiting ATP synthesis and disrupting cellular energy metabolism. Mutations in atpE and rv0678 can confer resistance to bedaquiline, with rv0678 mutations causing derepression of the MmpS5-MmpL5 efflux pump. While bedaquiline is highly effective, it carries clinical liabilities, most notably tissue accumulation and a risk of QT interval prolongation via hERG channel inhibition. TBAJ-876 (sorfequiline) and TBAJ-587 are next-generation diarylquinoline analogs designed with reduced lipophilicity to reduce tissue accumulation and minimize hERG interaction. Preclinical studies suggest greater antimycobacterial activity and a lower potential for QT prolongation than bedaquiline, while early clinical studies have characterized the analogs’ pharmacokinetics and safety. In preclinical and clinical pharmacokinetic studies, bedaquiline has also demonstrated CNS penetration and accumulation, suggesting its potential to target M. tuberculosis reservoirs in the CNS. The BPaL regimen, comprising bedaquiline, pretomanid, and linezolid, has demonstrated profound clinical efficacy against highly drug-resistant pulmonary TB, including XDR-TB and treatment-intolerant or nonresponsive MDR-TB [305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328,329,330,331,332].

Sudapyridine (WX-081). Sudapyridine is an investigational structural analog of bedaquiline with potent activity against drug-susceptible and drug-resistant M. tuberculosis, including MDR strains. Preclinical and clinical studies indicate a reduced potential for QT interval prolongation and improved pharmacokinetic properties compared with bedaquiline. Sudapyridine has advanced it into Phase III clinical trials for rifampicin-resistant (RR) pulmonary TB. Sudapyridine has also demonstrated in vitro, intracellular, and in vivo activity against NTM, including M. abscessus, M. avium, and Mycobacterium chelonae. Similar to bedaquiline, sudapyridine inhibits mycobacterial ATP synthase by targeting the c-ring and disrupts the proton motive force. It has also been reported to enhance innate immune responses via NF-κB and MAPK pathway activation in macrophage-based studies [333,334,335,336,337,338,339,340,341].

Q203 (Telacebec). Q203 is an investigational imidazopyridine amide that targets the QcrB subunit of the mycobacterial cytochrome bcc-aa₃ oxidase complex, thereby disrupting the electron transport chain and cellular respiration (Figure 2). It exhibits potent in vitro activity against drug-susceptible and drug-resistant M. tuberculosis, including MDR and XDR strains. It was evaluated clinically in patients with drug-susceptible pulmonary TB. Beyond TB, it has demonstrated exceptional clinical development potential against M. ulcerans and M. leprae, successfully advancing into Phase II clinical trials for Buruli ulcer and formal global development partnerships for leprosy [342,343,344,345,346].

BTZ-043. BTZ-043 is an investigational benzothiazinone derivative that covalently inhibits decaprenylphosphoryl-β-D-ribose 2′-epimerase 1 (DprE1), thereby blocking the biosynthesis of decaprenylphosphoryl-β-D-arabinose and, consequently, cell wall arabinan in M. tuberculosis (Figure 2). Having advanced into Phase IIb/c combination clinical trials for drug-susceptible pulmonary TB, BTZ-043 has also demonstrated preclinical activity against other Corynebacterineae, including Corynebacterium spp. and Nocardia spp. [347,348,349,350,351,352,353,354].

PBTZ169 (Macozinone). PBTZ169 is an investigational piperazine-containing benzothiazinone derivative that covalently inhibits the DprE1 enzyme of M. tuberculosis by binding to the C387 residue inside the active pocket, thereby blocking cell wall arabinan biosynthesis. Following the completion of safety, tolerability, and pharmacokinetic profiling in healthy volunteers, it has advanced into Phase II clinical evaluation as an early bactericidal candidate for shortened treatment regimens in patients with drug-susceptible pulmonary TB. Additionally, recent macrophage studies demonstrate that PBTZ169 enhances host innate immune responses by upregulating the NF-κB and MAPK signaling pathways [355,356,357].

Quabodepistat (OPC-167832). Quabodepistat is an investigational carbostyril derivative that inhibits DprE1, thereby blocking the biosynthesis of decaprenylphosphoryl-β-D-arabinose and, consequently, cell wall arabinan in M. tuberculosis. Following clinical evaluation for drug-susceptible pulmonary TB, it advanced into Phase III trials for MDR pulmonary TB. It also demonstrates in vitro bactericidal activity against M. abscessus. However, due to significantly lower relative potency against this NTM species, therapeutic efficacy was not observed in a mouse infection model, making it an unlikely candidate for NTM repurposing [358,359,360].

SQ109. SQ109 is an investigational N-geranyl-N′-(2-adamantyl)ethane-1,2-diamine structurally related to ethambutol, with activity against M. tuberculosis. Following early safety studies, SQ109 was evaluated in patients with drug-susceptible pulmonary TB and in a multicenter Phase IIb/III trial as part of a treatment regimen for MDR-TB. It acts by inhibiting the trehalose monomycolate transporter MmpL3 and disrupting the proton motive force, which impairs mycolic acid incorporation into the mycobacterial cell wall. In vitro bactericidal activity has also been reported against both drug-susceptible and drug-resistant strains of H. pylori [361,362,363,364,365,366].

Posizolid (AZD-5847, AZD-2563). Posizolid is an oxazolidinone that binds to the 50S ribosomal subunit and prevents formation of the translation-initiation complex, thereby inhibiting bacterial protein synthesis. It exhibits in vitro activity against a broad range of Gram-positive bacteria, particularly Staphylococcus spp., Streptococcus spp., and Enterococcus spp., including strains resistant to other antibiotic classes. Its in vitro antibacterial spectrum also includes Corynebacterium spp., Listeria spp., and Bacillus spp., Gram-positive anaerobes, and drug-susceptible and drug-resistant strains of M. tuberculosis. However, due to a high incidence of adverse hematologic and hepatic effects alongside modest effects compared to linezolid in a Phase II trial involving patients with drug-susceptible pulmonary TB, further development of posizolid has been discontinued [367,368,369,370,371].

Contezolid (MRX-I). Contezolid is a potent oxazolidinone with activity against Gram-positive pathogens, including MRSA, VRE, and other antibiotic-resistant strains. It has also demonstrated in vitro and preclinical activity against both drug-susceptible and drug-resistant strains of M. tuberculosis, as well as M. abscessus. Compared with linezolid, contezolid has a more favorable hematologic safety profile, including significantly lower incidences of leukopenia and thrombocytopenia in a Phase III trial. Because contezolid and linezolid both bind the peptidyl transferase center of the 50S ribosomal subunit, cross-resistance can occur in Gram-positive cocci carrying certain oxazolidinone-resistant determinants, although contezolid retains activity against some linezolid-resistant isolates. In contrast, contezolid-resistant M. tuberculosis mutants selected in vitro carried mce3R mutations and did not exhibit cross-resistance to linezolid. Contezolid is approved in China for complicated skin and soft tissue infections (cSSTIs), whereas its use for pneumonia and TB remains investigational or off-label [372,373,374,375,376,377,378,379,380].

Sutezolid (PNU-100480, U-100480, PF-02341272). Sutezolid is an investigational oxazolidinone that inhibits bacterial protein synthesis at the 50S ribosomal subunit and has greater antimycobacterial activity than linezolid in preclinical models against both drug-susceptible and drug-resistant strains of M. tuberculosis. Preclinical studies showed reduced mitochondrial toxicity with sutezolid compared with linezolid, and a Phase IIb clinical trial involving patients with drug-susceptible pulmonary TB demonstrated favorable tolerability, supporting its potential for an improved safety profile. Preclinical combination studies support the potential of sutezolid-containing regimens to shorten TB treatment, although this treatment-shortening efficacy remains under evaluation in a Phase IIc trial. Its antimycobacterial spectrum also includes M. avium complex, against which it shows in vitro activity, and M. ulcerans, against which it demonstrates activity in a mouse model of Buruli ulcer [381,382,383,384,385,386,387,388,389].

Pretomanid (PA-824). Pretomanid is an FDA-approved, oral nitroimidazooxazine indicated for use as part of combination therapy against drug-resistant M. tuberculosis (Figure 1). Its activity against both replicating bacilli and hypoxic, nonreplicating persisters contributes to its sterilizing activity and the treatment-shortening efficacy of pretomanid-containing regimens. As a prodrug, pretomanid requires activation by the deazaflavin-dependent nitroreductase (Ddn) and the reduced cofactor F₄₂₀H₂. Once activated, it exerts bactericidal activity through the release of reactive nitrogen species, including nitric oxide under hypoxic conditions, inhibition of mycolic acid biosynthesis, and disruption of respiratory bioenergetics. DprE2, which is involved in decaprenylphosphoryl-β-D-arabinose biosynthesis and consequently in arabinogalactan synthesis, has also been proposed as a molecular target. Resistance is primarily mediated by mutations in ddn, fgd1, fbiA, fbiB, fbiC, and fbiD, which impair prodrug activation, F₄₂₀ biosynthesis, or cofactor reduction. Pretomanid is a key component of the BPaL and BPaLM (bedaquiline, pretomanid, linezolid, and moxifloxacin) regimens used to treat indicated forms of MDR and RR pulmonary TB, including fluoroquinolone-resistant disease when moxifloxacin is omitted. BPaMZ (bedaquiline, pretomanid, moxifloxacin, and pyrazinamide) remains an investigational regimen, and pretomanid has also been evaluated in treatment-shortening regimens for drug-susceptible TB. Preclinical studies have explored pretomanid-containing regimens for CNS-TB, but their clinical efficacy for this indication has not been established. Delamanid is another nitroimidazole used for drug-resistant TB in selected clinical settings [316,326,390,391,392,393,394,395,396,397,398,399,400,401,402,403,404,405,406].

Delamanid (OPC-67683, Deltyba). Delamanid is a nitroimidazooxazole prodrug with activity against drug-susceptible and drug-resistant strains of M. tuberculosis, including MDR and rifampicin-resistant strains. It is used as part of combination regimens for adults and children with MDR/RR-TB. However, evidence supporting its use in extrapulmonary and CNS-TB remains limited and is derived mainly from pharmacokinetic studies, observational reports, and case series. It inhibits the biosynthesis of methoxy- and keto-mycolic acids. As a prodrug, it is activated by Ddn using reduced F₄₂₀. Its activated metabolites also inhibit DprE2, disrupting cell wall arabinan biosynthesis, while reactive nitrogen species can also contribute to its antibacterial activity. Mutations in ddn, fgd1, fbiA, fbiB, fbiC, and fbiD confer resistance by impairing F₄₂₀ biosynthesis or reduction or preventing delamanid activation. Delamanid has demonstrated antitubercular efficacy when incorporated into multidrug regimens and is included in the six-month BDLLfxC regimen (bedaquiline, delamanid, linezolid, levofloxacin, and clofazimine) for MDR/RR-TB. Bedaquiline-, delamanid-, and linezolid-containing regimens have also been used as individualized salvage therapy in selected patients with highly drug-resistant TB [401,405,407,408,409,410,411,412,413,414,415,416,417,418,419,420].

Notably, the development of antimycobacterial drugs reflects substantial progress in targeting essential pathways involved in energy metabolism, cell wall biosynthesis, and protein synthesis (Table 1). The successful development of bedaquiline and pretomanid, together with investigational antibacterials such as sudapyridine, Q203, BTZ-043, PBTZ169, quabodepistat, SQ109, and newer oxazolidinones, underscores the therapeutic potential of diverse targets and mechanisms of action against TB, including drug-resistant TB. Their incorporation into combination regimens and the continued development of safer and more potent treatments are important strategies for addressing drug resistance, reducing toxicity, and shortening TB treatment.

2.5. Nontraditional Treatments

iOWH032. iOWH032 is a synthetic small-molecule inhibitor of the cystic fibrosis transmembrane conductance regulator chloride channel investigated as an oral, antisecretory, host-directed treatment for cholera caused by Vibrio cholerae. In a Phase IIa controlled human infection study, iOWH032 did not significantly reduce diarrheal stool output or the severity of diarrhea compared with placebo, and its development was discontinued [421].

Ribaxamase (SYN-004, P3A, derived from P1A). Ribaxamase is a first-in-class, recombinant β-lactamase that degrades susceptible β-lactam antibiotics. When administered orally in conjunction with intravenous β-lactam antibiotics, it is designed to protect the gut microbiome from antibiotic-induced disruption by degrading excess antibiotics excreted via the biliary route into the small intestine. In a Phase IIb trial involving patients receiving intravenous ceftriaxone, ribaxamase was associated with a lower incidence of C. difficile infection than placebo, while enrollment in a subsequent trial is currently paused. Its ability to prevent other antibiotic-associated diarrhea has not been established [422,423,424].

These nontraditional treatments represent host-directed and microbiome-protective approaches (Table 1), although establishing clinical benefit remains challenging. Further exploration of nontraditional strategies, including antibacterials guided by bacterial physiology and pathogenesis, is needed to expand options for preventing and treating bacterial infections.

3. Future Outlook

Antibacterial development since 2010 encompasses improvements to established antibiotic classes, new β-lactam/β-lactamase inhibitor combinations, siderophore cephalosporins, antibiotic hybrids, antibody-antibiotic conjugates, narrow-spectrum antibacterials, and antibacterials with novel chemical scaffolds, targets, and mechanisms of action. Despite this encouraging progress, the rate at which antibiotic resistance is emerging continues to outpace antibacterial development, necessitating greater investment in antibacterial discovery and development. The successful clinical translation and FDA approval of gepotidacin, zoliflodacin, bedaquiline, and pretomanid represent important milestones and provide valuable lessons for future antibacterial development. Future efforts should prioritize advancing promising antibacterials with novel targets or mechanisms of action, such as ibezapolstat, CRS3123, BTZ-043, and Q203. Innovative antibacterial designs that incorporate multiple targets or mechanisms of action, together with targeted antibiotic delivery, offer opportunities to enhance antibacterial activity, improve selectivity, and overcome the limitations of conventional antibiotics. Machine learning and artificial intelligence-guided methods have the potential to accelerate antibacterial discovery and development [425]. Lessons from discontinued development programs suggest that early assessment of resistance potential and safety, together with rigorous evaluation of clinical efficacy, can improve the likelihood of successful antibacterial development. However, antibiotic resistance is too complex to be addressed solely through the discovery of new antibacterials. Therefore, nontraditional treatments, such as anti-virulence therapies, host-directed therapies, microbiome-based therapeutics, antibiotic adjuvants, phage therapy, and monoclonal antibodies, should also be explored. Finally, antibiotic stewardship remains a priority, and the implementation of One Health approaches is essential to curb the emergence and spread of antibiotic resistance.