Search Results (145)

Objective: Linezolid (LZD), an oxazolidinone antibiotic widely used against Gram-positive infections, has been associated with mitochondrial dysfunction and hepatotoxicity, particularly during prolonged use. This study aimed to investigate the protective effects of adenosine triphosphate (ATP) and Liv-52 against LZD-induced liver injury, with a focus on oxidative stress, inflammation, and necroptosis pathways. Methods: Twenty-four male Wistar rats were randomly assigned to four groups: healthy control (HG), LZD-treated (LZDG), Liv-52 + LZD (LVLZ), and ATP + LZD (ATLZ). Liv-52 (50 mg/kg, orally) and ATP (5 mg/kg, intraperitoneally) were administered prior to LZD (125 mg/kg, orally) for 14 days. Results: Following LZD administration, malondialdehyde (MDA) levels markedly increased, indicating oxidative stress, while total glutathione (tGSH), superoxide dismutase (SOD), and catalase (CAT) activities significantly decreased. Histopathological examination revealed pronounced hepatocellular damage accompanied by increased NF-κB, NLRP3, RIPK3, and MLKL expression, indicating activation of inflammatory and necroptotic pathways. Treatment with ATP and Liv-52 significantly ameliorated these biochemical, histopathological, and molecular alterations. Conclusions: Treatment with ATP and Liv-52 significantly attenuated oxidative stress, improved histopathological alterations, and suppressed the expression of inflammatory and necroptotic markers. Notably, ATP exhibited a more pronounced protective effect compared to Liv-52. In conclusion, LZD induces hepatotoxicity through oxidative stress-mediated inflammatory and necroptotic mechanisms, while ATP and Liv-52 confer hepatoprotection, with ATP showing superior efficacy. Full article

Linezolid represents a critical last-resort treatment for severe multidrug-resistant (MDR) Gram-positive bacterial infections. Rising linezolid resistance in Enterococcus isolates threatens its efficacy; this study characterized the molecular features and transfer potential of plasmid-encoded linezolid resistance genes optrA and poxtA in a linezolid-resistant Enterococcus asini isolate from chickens. An E. asini strain was isolated during a surveillance program focusing on drug-resistant Gram-positive bacteria in poultry. PCR screened linezolid resistance genes, conjugation and plasmid stability assays evaluated gene transferability and stability, and whole-genome sequencing (WGS) was performed using both the Illumina and Nanopore platforms. We present the first detection of optrA and poxtA genes in E. asini recovered from chicken feces in China. Sequence analysis of the complete genome showed that poxtA and optrA were situated on two distinct plasmids. The poxtA positive plasmid, pHNGXN23C145Ea-1, also carried multiple resistance genes, including tet(S), fexB, erm(B), ant(6)-Ia, aph(3′)-III. Furthermore, the poxtA gene was flanked by IS1216E mobile elements. The optrA bearing plasmid, pHNGXN23C145Ea-2, harbours a common genetic array of ‘IS1216E fexA-optrA-erm(A)-IS1216E’. Conjugation experiments indicated that neither the poxtA- nor the optrA-bearing plasmid was transferred to recipient strains, which was consistent with sequence analysis showing that both plasmids lacked intact conjugative transfer regions. Stability assays confirmed that poxtA and optrA remained highly stable in the absence of selective pressure. Notably, this discovery was made in a livestock sample, despite the non-use of linezolid in food animals, suggesting that such niches may act as silent reservoirs for resistance genes, which could persist and potentially transfer to clinically relevant MDR pathogens. Full article

In the last three decades, 2-oxazolidinones have emerged as an important class of inhibitors of bacterial protein synthesis, effective in the treatment of multidrug-resistant (MDR) bacterial infections. From a public health perspective, the importance of 2-oxazolidinones is related to the treatment of tuberculosis (TB), primarily MDR-TB and extensively drug-resistant XDR-TB. Linezolid, the first oxazolidinone antibiotic approved by FDA, is still used in therapy despite common adverse events, such as myelosuppression and serotonergic toxicity, as well as the increasing percentage of linezolid-resistant bacteria (Staphylococcus aureus, enterococci and methicillin-resistant S. aureus). Tedizolid phosphate was the second commercially available oxazolidinone antibiotic approved, followed by other oxazolidinones (contezolid, radezolid, ranbezolid, sutezolid, delpazolid, cadazolid, TBI-233 and MK-7762) that are in clinical study. Contezolid is approved in China and cadazolid has entered phase III clinical trials. This comprehensive review intends to provide an overview of the compounds belonging to this class already in use in therapy and/or clinical studies and to portray the most significant and recent outcomes regarding new oxazolidinones under study. Three literature databases, i.e., PubMed/MEDLINE, Google Scholar and Scopus, were used for the literature search, particularly focusing on the last five years, and screened using different keywords. The design of new drugs belonging to this class may be of considerable interest to researchers and clinicians, contributing to the discovery of new antibiotics that retain antibacterial activity but have fewer side effects. Full article

Background/Objectives: Linezolid is an oxazolidinone antibiotic whose prolonged use is associated with peripheral neuropathy, hyperlactatemia, and metabolic acidosis. These adverse effects are primarily linked to the inhibition of mitochondrial protein synthesis, respiratory chain dysfunction, and oxidative stress. Given the central role of impaired energy metabolism and redox imbalance in drug-induced peripheral neuropathy, therapeutic strategies targeting mitochondrial function are of particular interest. Accordingly, this study aimed to comparatively evaluate the effects of adenosine triphosphate (ATP), coenzyme Q10 (CoQ10), pyridoxine, and thiamine pyrophosphate (TPP) on linezolid-induced peripheral neuropathic pain in rats. Methods: Sixty male albino Wistar rats were assigned to ten groups: healthy (HG); ATP-only (ATPG, 5 mg/kg, intraperitoneally); CoQ10-only (CQ10G, 10 mg/kg, orally); pyridoxine-only (PDXG, 50 mg/kg, orally); TPP-only (TPPG, 20 mg/kg, intraperitoneally); linezolid-only (LZDG, 125 mg/kg, orally); linezolid+ATP (ATLG); linezolid+CoQ10 (CQLG); linezolid+pyridoxine (PXLG); and linezolid+TPP (TPLG). Treatments were administered once daily for ATP, CoQ10, and TPP, and twice daily for linezolid and pyridoxine for 14 days. Oxidative stress indices (MDA, tGSH, SOD, CAT) were quantified in the sciatic nerve using ELISA. Serum lactate dehydrogenase (LDH) activity and blood lactate levels were determined to evaluate metabolic disturbances. Mechanical paw withdrawal thresholds were measured using the Randall–Selitto test both before and after treatment. Results: Linezolid significantly reduced paw withdrawal thresholds and induced oxidative stress, antioxidant depletion, increased LDH activity, and hyperlactatemia. Co-treatment with ATP and CoQ10 attenuated oxidative stress but did not significantly improve linezolid-induced reductions in nociceptive thresholds. In contrast, pyridoxine partially alleviated linezolid-induced neuropathic pain and improved biochemical parameters. Notably, TPP exerted the most robust protective effect, preserving nociceptive thresholds and effectively normalizing oxidative stress and metabolic indices. Conclusions: These findings identify TPP as a promising therapeutic strategy for mitigating linezolid-induced peripheral neuropathic pain by targeting mitochondrial energy metabolism and pyruvate–lactate homeostasis. Full article

Background: Oxazolidinone derivatives are a novel class of synthetic antibacterial agents, characterized by a five-membered heterocyclic ring containing oxygen and nitrogen and a carbonyl functionality at position 2. This pharmacophore is responsible not only for antibacterial activity but also for a variety of other biological activities, including anticancer activity, anticoagulant activity, and several others. A series of novel oxazolidinone derivatives containing a hydroxamic acid moiety were synthesized in our laboratories and identified as potent inhibitors of the enzyme 5-lipoxygenase (5-LO), a key enzyme involved in the biosynthesis of leukotrienes (LTs). LTs are proinflammatory mediators implicated in allergic and inflammatory diseases. Currently, zileuton is the only FDA-approved 5-LO inhibitor, emphasizing the need to develop new agents for the treatment of such diseases. This project aims to develop validated stability-indicating analytical methods for the four most potent novel 5-(hydroxamic acid)methyl oxazolidinone derivatives (PH-211, PH-247, PH-249, and PH-251). Methods: The compounds were analyzed using Waters Acquity Ultra-High-Performance Liquid Chromatography (UHPLC-UV) with an ultraviolet detector to determine their stability in human plasma and under various forced degradation conditions, including acidic, basic, oxidative, and thermal conditions. Liquid chromatography–quadrupole time-of-flight mass spectrometry (LC-QToF-MS) was used to identify possible degradation products. Results: The compounds were found to be stable in human plasma and under thermal degradation conditions with high extraction recoveries (82–90%) but unstable in acidic, basic, and oxidative conditions. Conclusions: The findings show that the compounds are stable in biological conditions; they hold promise for the treatment of inflammatory and allergic diseases. Full article

Antimicrobial resistance remains a critical global health challenge, and was intensified by the COVID-19 pandemic. To address this growing threat, novel antibacterial agents targeting unconventional mechanisms are urgently needed. One promising strategy involves inhibiting bacterial riboswitches—RNA elements that regulate gene expression. Unlike most riboswitches that respond to small-molecule metabolites, the T-box riboswitch uniquely binds non-aminoacylated tRNA and is predominantly found in Gram-positive bacteria, making it an attractive target due to its conserved sequences and regulatory role over essential genes. This study explored oxazolidinone- and triazole-based compounds as potential inhibitors of the T-box riboswitch. Prior investigations into tricyclic oxazolidinones revealed an allosteric modulator that effectively inhibited T-box riboswitch transcriptional readthrough in vitro, though it showed limited disruption of the isolated tRNA–antiterminator complex. To enhance RNA-binding affinity and stereoselectivity, a macrocyclic oxazolidinone scaffold was designed, incorporating a strategic substituent to expand the interaction footprint. A synthetically viable candidate was identified, and computational docking studies suggested that one of the designed compounds may interfere with tRNA-induced transcription by forming π–π stacking interactions with G5 in the antiterminator region. These findings support the potential of targeting the T-box riboswitch with structurally optimized small molecules as a novel antibacterial strategy. Full article

Linezolid (LZD) is an oxazolidinone antibiotic effective in the treatment of infection with Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The decline in susceptibility to linezolid is a concern for antimicrobial chemotherapy. In this study, the prevalence of the LZD minimum inhibitory concentration (MIC) of 2 mg/L (LZD-MIC2), which represents a slightly high value within a range of susceptibility for S. aureus (≤4 mg/L), was investigated retrospectively for staphylococcal species from different sources. We collected the records of LZD MIC of Staphylococcus/Mammaliicoccus that had been obtained in our previous studies on isolates from patients, healthy individuals, and foodstuff. Prevalence of isolates showing LZD-MIC2 was analyzed depending on the type of staphylococcal species and S. aureus clones. In clinical isolates, methicillin-susceptible S. aureus (MSSA) and S. argenteus showed significantly higher LZD-MIC2 rates (20.0% and 21.5%, respectively) than MRSA (7.3%). Among clinical and colonizing isolates of MSSA, LZD-MIC2 was more commonly found in CC1 (ST188, ST2990, etc.), CC8, CC15, ST30, ST97, and ST121 than other lineages. In S. argenteus isolates, which were mostly methicillin-susceptible, there was no significant difference in the LZD-MIC2 prevalence among the three genotypes. The LZD-MIC2 was detected in 18.3% of coagulase-negative staphylococci (CoNS), with S. saprophyticus, S. pasteuri, and M. sciuri showing higher prevalence (30–57%) than other species. The present study revealed that the prevalence of the LZD-MIC2 is different depending on staphylococcal species/types, as they are more common in specific MSSA lineages and some CoNS species. Full article

Background/Objectives: Linezolid is a first-in-class oxazolidinone antibiotic that exhibits activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. However, its clinical use is often restricted because of hematological toxicities, particularly thrombocytopenia, in patients with renal impairment. That side effect is thought to result from the systemic accumulation of pharmacologically inactive metabolites generated by oxidative degradation and ring-opening of the morpholine, but the details remain unclear. In this study, we established a novel synthetic route for four linezolid metabolites (PNU-142618, 142300, 142586 and 173558). Methods: The four major metabolites, which are secondary or tertiary amines, were synthesized using the aniline derivatives protected with a 2-nitrobenzensulfonyl (Ns) group. Results: Application of this Ns strategy enabled selective N-alkylation, enabling efficient synthesis of the target metabolites. The desired metabolites containing a carboxylic acid group were obtained as their sodium salts. This is the first report on the synthesis of PNU-142618 and 173558. Conclusions: The established synthetic pathway provides access to four linezolid metabolites. The results facilitated the provision of compounds necessary for comprehensive pharmacokinetic and toxicological studies. Full article

Non-tuberculous mycobacteria (NTM) comprise more than 190 species capable of causing severe pulmonary, lymphatic, cutaneous, and disseminated infections, particularly in immunocompromised populations. Over the past two decades, the global incidence of NTM infections has risen steadily, underscoring an urgent unmet medical need. Treatment remains highly challenging due to intrinsic antimicrobial resistance and the requirement for prolonged multidrug regimens that are often poorly tolerated and associated with unsatisfactory outcomes. At the same time, the development of novel therapies has lagged behind other disease areas, hindered by the high costs of antimicrobial drug discovery and the relatively low commercial return compared with treatments for chronic conditions. Over the past decade, discovery and development have diversified across novel small molecules, next-generation analogues of existing classes, and adjunctive or host-directed strategies. While most candidates remain preclinical, several agents have advanced clinically in other infections, including gepotidacin (topoisomerase inhibitor; FDA-approved 2025 for urinary tract infection (UTI)), sulbactam–durlobactam (DBO β-lactamase inhibitor; FDA-approved 2023 for Acinetobacter baumannii complex), and contezolid, supporting repurposing opportunities for NTM. Conversely, SPR720 (gyrase B prodrug) was suspended after not meeting its Phase 2 endpoint in 2024, underscoring translational risk. Overall, the NTM pipeline is expanding, with near-term progress most likely from repurposed agents and optimised combinations, alongside earlier-stage candidates that target biofilms or resistance mechanisms. This review aims to provide a critical and up-to-date overview of emerging antimicrobial strategies against NTM, highlighting recent advances, translational challenges, and opportunities to accelerate the development of effective therapeutics. Full article

Tuberculosis (TB) persists as a formidable global health threat, especially with the rising incidence of multidrug-resistant strains. This study aimed to evaluate the in vitro activity of contezolid, a novel oxazolidinone antibiotic, against Mycobacterium tuberculosis (Mtb) and assess potential cross-resistance with linezolid. Thirty-one Mtb clinical isolates (5 susceptible, 8 multidrug-resistant [MDR], 18 pre-extensively drug-resistant [pre-XDR]) were tested. Minimum inhibitory concentrations (MICs) of contezolid and linezolid were determined, along with mutation resistance frequencies. Intracellular replication inhibition in macrophages and whole-genome sequencing of resistant colonies were assessed. Cytotoxicity was evaluated via luciferase-coupled ATP assay. The MIC50 and MIC90 values of contezolid were comparable to those of linezolid. Contezolid induced higher mutation frequencies in 7 isolates. At 12 mg/L, both drugs similarly inhibited intracellular Mtb replication. Whole-genome sequencing revealed that the mce3R gene was linked to contezolid resistance, with no cross-resistance observed between two drugs. No significant cytotoxicity was observed in contezolid-treated mouse peritoneal macrophages (p > 0.05). Contezolid exhibits anti-Mtb activity, with mce3R potentially associated with resistance. No cross-resistance with linezolid was found. Full article

Background: The emergence of livestock-associated antimicrobial-resistant staphylococci, particularly non-aureus staphylococci, has become a major public health problem requiring immediate global attention. Methods: In this study, 92 Staphylococcus borealis isolates from 20 different pig farms in Korea were examined to determine the following: (1) antimicrobial-resistance (AMR) profiles of the isolates, (2) prevalence of methicillin resistance and staphylococcal cassette chromosome methicillin resistance gene (SCCmec) types, (3) occurrence of chloramphenicol–florfenicol resistance gene (cfr)-mediated oxazolidinone resistance, and (4) genomic characteristics of cfr-positive methicillin-resistant S. borealis (MRSB) via whole-genome sequence (WGS) analysis. Results: The overall rate of S. borealis isolation was 9.1% (92 isolates/1009 swabs), and 34.8% (32/92) of the isolates were MRSB. Surprisingly, all 32 MRSB isolates carried SCCmec V for methicillin resistance, and 31/32 MRSB isolates displayed multidrug-resistance phenotypes. Although 22 cfr-positive S. borealis isolates (20 MRSB and two methicillin-susceptible S. borealis) were identified, most of the isolates were susceptible to linezolid because they carried the 35-bp insertion sequence in the cfr promoter. Moreover, WGS analyses suggested horizontal transmission of SCCmec V and cfr-containing plasmids among different staphylococci species, including Staphylococcus aureus, S. epidermidis, and S. borealis. Conclusions: To the best of our knowledge, this study is the first to describe the AMR characteristics of livestock-associated S. borealis isolates, particularly the high prevalence of SCCmec V and cfr. Collectively, these results suggest that S. borealis is a crucial reservoir of AMR genes on pig farms in Korea. Full article

Vagococcus lutrae is an emerging pathogen that can cause severe disease, especially in immunocompromised patients. Unlike Vagococcus fluvialis, which is recognized as a human and animal pathogen, there are few reports of V. lutrae from human and animal infections. In humans, it has been reported in patients with severe skin lesions and bloodstream infections. In veterinary medicine, V. lutrae was accidentally isolated from a Eurasian otter and a largemouth bass, and only once from the genitourinary tract of a pig with a urinary tract infection. However, the prevalence may be underestimated due to difficulties in identification using traditional methods. In addition, V. lutrae could be a carrier of resistance genes and contribute to the spread of AMR. A neutered male cat with feline urological syndrome underwent urethrostomy surgery due to serious problems with dysuria and urolithiasis that could not be resolved through catheterizations. Urine culture revealed the presence of Vagococcus lutrae. The strain showed resistance genes against aminoglycoside, lincosamide, streptogramin a and b, pleuromutilin, macrolide, tetracycline, oxazolidinone, and amphenicol classes. We report the first isolation of V. lutrae from the urinary tract of a cat. Full article

The emergence of extensively drug-resistant (XDR) foodborne pathogens poses grave threats to food safety. This study characterizes the genome of an XDR Salmonella Kentucky isolate (Sal23C1) co-harboring cfr, mcr-1 and tet(A) from Shanghai chicken meat in 2022, which was the only isolate co-harboring these three key resistance genes among 502 screened Salmonella isolates. Genomic analysis revealed that the multidrug resistance gene cfr, which confers resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins and streptogramin A, was identified within a Tn3-IS6-cfr-IS6 structure on the transferable plasmid p3Sal23C1 (32,387 bp), showing high similarity to the Citrobacter braakii plasmid pCE32-2 (99% coverage, 99.98% identity). Concurrently, the mcr-1 gene resided in a pap2-mcr-1 structure on the transferable IncI2 plasmid p2Sal23C1 (63,103 bp). Notably, both genes could be co-transferred to recipient bacteria via conjugative plasmids at frequencies of (1.15 ± 0.98) × 10⁻⁶. Furthermore, a novel ~79 kb multidrug resistance region (MRR) chromosomally inserted at the bcfH locus was identified, carrying fosA3, mph(A), rmtB, qnrS1 and bla_CTX-M-55. Additionally, a novel Salmonella Genomic Island 1 variant (SGI1-KI) harbored aadA7, qacEΔ1, sul1 and the tet(A) variant. The acquisition of these antibiotic resistance genes in this isolate enhanced bacterial resistance to 21 antimicrobials, including resistance to the critical last-resort antibiotics tigecycline and colistin, which left virtually no treatment options for potential infections. Taken together, this is the first comprehensive genomic report of an XDR poultry-derived Salmonella Kentucky isolate co-harboring cfr, mcr-1 and the tet(A) variant. The mobility of these resistance genes, facilitated by IS6 elements and conjugative plasmids, underscores significant public health risks associated with such isolates in the food chain. Full article

Linezolid (LNZ) is a synthetic oxazolidinone antibiotic that inhibits bacterial protein synthesis through binding to ribosomal RNA, also preventing the assembly of the initiation complex during translation. It is one of the last-line therapeutic options for serious infections caused by problematic Gram-positive pathogens, including vancomycin-resistant and multidrug-resistant Enterococcus species. Data from recent large-scale studies show a 2.5-fold increase in the prevalence of clinical LNZ-resistant enterococci (LRE) over the past decade with a global detection rate of 1.1% for LNZ-resistant E. faecium (LREfm) and 2.2% for LNZ-resistant E. faecalis (LREfs). Most reported cases have originated from China, followed by South Korea and the United States. LREfm typically belongs to the high-risk clonal complex 17, whereas LREfs demonstrates a heterogeneous population structure. Mutations in the 23S rRNA and ribosomal proteins, as well as acquired resistance genes such as cfr, optrA, and poxtA are involved in the development of LNZ resistance among enterococci. Whole-genome sequencing (WGS) has been recognized as a gold standard for identifying the underlying molecular mechanisms. It exposes that numerous LRE isolates possess multiple LNZ resistance determinants and mutations, further complicating the treatment strategies. The present review article summarizes all known mutational and non-mutational LNZ resistance mechanisms and presents a global overview of WGS-based studies with emphasis on resistome analysis of clinical LREfs and LREfm isolates published in the literature during the period 2014–2025. Full article

Background: Broad-spectrum antibiotics are often used for suspected infections in patients with hematologic malignancies due to the risk of severe infections. Although antibiotic use can lead to antimicrobial resistance and microbiome dysbiosis, the effects of antibiotics on the microbiome and resistome in patients with acute myeloid leukemia (AML) undergoing remission induction chemotherapy (RIC) are not well understood. Methods: Various statistical models were utilized to examine the effects of antibiotic administration on the microbiome and resistome over time, as well as differences in AR-infection (ARI) and colonization (ARC) by important CDC-threats in 119 AML patients. Results: A greater number of unique antibiotic classes administered correlated with a loss of unique antibiotic resistance genes (ARGs) (R = −0.39, p = 0.008). Specifically, although a greater number of oxazolidinone administrations was correlated with a greater loss of diversity (R = −0.58, p < 0.001), each additional day of linezolid reduced the risk of ARC by ~30% (HR: 0.663, p = 0.047) and decreased the odds of acquiring genes predicted to confer macrolide (HR: 0.50, p = 0.026) resistance. Conclusions: The number of antibiotic administrations and the types of antibiotics used can influence the risk of antibiotic resistance gene (ARG) expansion and ARC events in AML patients undergoing RIC. While certain antibiotics may reduce microbial diversity, they are not always linked to an increase in ARGs or ARC events. Full article