Novel Antimicrobial Agents: Design, Synthesis and Biological Evaluation

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Novel Antimicrobial Agents".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 22039

Special Issue Editor

The Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
Interests: antibiotics; drug design; Mur ligases; cell wall; medicinal chemistry;peptidoglycan; computer-aided drug design; machine learning
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Although most bacterial infections can now be effectively controlled with the available arsenal of antibiotics, the emergence of antibiotic resistance (AMR) has led to less effective infection management and higher healthcare costs, longer hospital stays, and higher mortality rates. The World Health Organization (WHO) estimated that the number of deaths directly caused by antimicrobial-resistant pathogens will increase to 10 million per year worldwide by 2050, making AMR one of the most life-threatening problems facing humanity.

Over the past 30 years, modern antibacterial drug development has faced an extraordinarily low output of new antibacterial drugs. Moreover, only a quarter of the potential antibacterial agents in preclinical trials belong to a new class or act via a new mechanism.

On the other hand, many new cutting-edge technologies developed in the last two decades have not yet succeeded in improving the performance of clinical pipelines for antibacterial agents. Although much creativity has been invested in new screening techniques and computer-aided drug design, most new antibacterial agents have been discovered via the chemical optimization of existing agents or by chance.

This Special Issue hopes to receive manuscripts that can be broadly classified as addressing the field of the medicinal chemistry of antibacterial compounds. In particular, traditional approaches as well as computational drug design, from target identification to machine learning techniques in discovery, are desired. Although we hope to receive manuscripts that describe the design and preparation of new classes of antibacterial agents with novel mechanisms of action, we will also accept manuscripts that describe the chemical synthesis and optimization of existing antibacterial agents, both semisynthetic and fully synthetic.

Dr. Rok Frlan
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antibacterials
  • organic synthesis
  • medicinal chemistry
  • computer-aided drug design
  • machine learning
  • deep learning
  • antibiotics
  • targets
  • drug design
  • optimization

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Published Papers (12 papers)

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Research

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27 pages, 4953 KiB  
Article
Navigating the Chemical Space of ENR Inhibitors: A Comprehensive Analysis
by Vid Kuralt and Rok Frlan
Antibiotics 2024, 13(3), 252; https://doi.org/10.3390/antibiotics13030252 - 11 Mar 2024
Cited by 1 | Viewed by 1099
Abstract
Antimicrobial resistance is a global health threat that requires innovative strategies against drug-resistant bacteria. Our study focuses on enoyl-acyl carrier protein reductases (ENRs), in particular FabI, FabK, FabV, and InhA, as potential antimicrobial agents. Despite their promising potential, the lack of clinical approvals [...] Read more.
Antimicrobial resistance is a global health threat that requires innovative strategies against drug-resistant bacteria. Our study focuses on enoyl-acyl carrier protein reductases (ENRs), in particular FabI, FabK, FabV, and InhA, as potential antimicrobial agents. Despite their promising potential, the lack of clinical approvals for inhibitors such as triclosan and isoniazid underscores the challenges in achieving preclinical success. In our study, we curated and analyzed a dataset of 1412 small molecules recognized as ENR inhibitors, investigating different structural variants. Using advanced cheminformatic tools, we mapped the physicochemical landscape and identified specific structural features as key determinants of bioactivity. Furthermore, we investigated whether the compounds conform to Lipinski rules, PAINS, and Brenk filters, which are crucial for the advancement of compounds in development pipelines. Furthermore, we investigated structural diversity using four different representations: Chemotype diversity, molecular similarity, t-SNE visualization, molecular complexity, and cluster analysis. By using advanced bioinformatics tools such as matched molecular pairs (MMP) analysis, machine learning, and SHAP analysis, we were able to improve our understanding of the activity cliques and the precise effects of the functional groups. In summary, this chemoinformatic investigation has unraveled the FAB inhibitors and provided insights into rational antimicrobial design, seamlessly integrating computation into the discovery of new antimicrobial agents. Full article
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14 pages, 3521 KiB  
Article
Design, Synthesis, Antimicrobial Properties, and Molecular Docking of Novel Furan-Derived Chalcones and Their 3,5-Diaryl-∆2-pyrazoline Derivatives
by Inas S. Mahdi, Ahmed Mutanabbi Abdula, Abdulkadir M. Noori Jassim and Younis Baqi
Antibiotics 2024, 13(1), 21; https://doi.org/10.3390/antibiotics13010021 - 24 Dec 2023
Cited by 2 | Viewed by 1462
Abstract
The present work focuses on the synthesis and preliminary structure activity relationships (SARs) of furan-derived chalcones and their corresponding ∆2-pyrazoline derivatives as antimicrobial agents. Eight novel chalcone derivatives and eight ∆2-pyrazoline compounds were synthesized in moderate to good isolated [...] Read more.
The present work focuses on the synthesis and preliminary structure activity relationships (SARs) of furan-derived chalcones and their corresponding ∆2-pyrazoline derivatives as antimicrobial agents. Eight novel chalcone derivatives and eight ∆2-pyrazoline compounds were synthesized in moderate to good isolated yields. The target compounds were evaluated as antimicrobial agents against two Gram-positive (Staphylococcus aureus and Staphylococcus epidermidis), two Gram-negative (Escherichia coli and Klebsiella pneumoniae), and fungi (Candida albicans) species. Based on the SARs, chalcones 2a and 2h showed inhibition activity on all tested microbial species, while ∆2-pyrazoline 3d was found to be selective for some microbial species. The most potent compounds (2a, 2h, and 3d) were docked into glucosamine-6-phosphate synthase (GlcN-6-P), the molecular target enzyme for antimicrobial agents, utilizing the Autodock 4.2 program, in order to study their virtual affinity and binding mode with the target enzyme. The selected potent compounds were found to bind to the active site of the enzyme probably in a similar way to that of the substrate as suggested by the docking study. In summary, the newly developed furan-derived chalcones and their ∆2-pyrazoline derivatives could serve as potent leads toward the development of novel antimicrobial agents. Full article
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7 pages, 711 KiB  
Communication
SK-03-92 Drug Kills Intracellular Mycobacterium tuberculosis
by William R. Schwan
Antibiotics 2023, 12(9), 1385; https://doi.org/10.3390/antibiotics12091385 - 30 Aug 2023
Cited by 1 | Viewed by 1098
Abstract
Background: Tuberculosis affects millions of people worldwide. The emergence of drug-resistant Mycobacterium tuberculosis strains has made treatment more difficult. A drug discovery project initiated to screen natural products identified a lead stilbene compound, and structure function analysis of hundreds of analogs led to the [...] Read more.
Background: Tuberculosis affects millions of people worldwide. The emergence of drug-resistant Mycobacterium tuberculosis strains has made treatment more difficult. A drug discovery project initiated to screen natural products identified a lead stilbene compound, and structure function analysis of hundreds of analogs led to the discovery of the SK-03-92 stilbene lead compound with activity against several non-tuberculoid mycobacteria. Methods: For this study, an MIC analysis and intracellular killing assay were performed to test SK-03-92 against M. tuberculosis grown in vitro as well as within murine macrophage cells. Results: The MIC analysis showed that SK-03-92 had activity against M. tuberculosis in the range of 0.39 to 6.25 μg/mL, including activity against single-drug-resistant strains. Further, an intracellular kill assay demonstrated that the SK-03-92 lead compound killed M. tuberculosis cells within murine macrophage cells. Conclusion: Together, the data show the SK-03-92 lead compound can kill M. tuberculosis bacteria within mammalian macrophages. Full article
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21 pages, 5831 KiB  
Article
Synthesis of Novel Quinazolinone Analogues for Quorum Sensing Inhibition
by Sahil Shandil, Tsz Tin Yu, Shekh Sabir, David StC. Black and Naresh Kumar
Antibiotics 2023, 12(7), 1227; https://doi.org/10.3390/antibiotics12071227 - 24 Jul 2023
Cited by 3 | Viewed by 1383
Abstract
As bacteria continue to develop resistance mechanisms against antimicrobials, an alternative method to tackle this global concern must be developed. As the pqs system is the most well-known and responsible for biofilm and pyocyanin production, quinazolinone inhibitors of the pqs system in P. [...] Read more.
As bacteria continue to develop resistance mechanisms against antimicrobials, an alternative method to tackle this global concern must be developed. As the pqs system is the most well-known and responsible for biofilm and pyocyanin production, quinazolinone inhibitors of the pqs system in P. aeruginosa were developed. Molecular docking following a rationalised medicinal chemistry approach was adopted to design these analogues. An analysis of docking data suggested that compound 6b could bind with the key residues in the ligand binding domain of PqsR in a similar fashion to the known antagonist M64. The modification of cyclic groups at the 3-position of the quinazolinone core, the introduction of a halogen at the aromatic core and the modification of the terminal group with aromatic and aliphatic chains were investigated to guide the synthesis of a library of 16 quinazolinone analogues. All quinazolinone analogues were tested in vitro for pqs inhibition, with the most active compounds 6b and 6e being tested for biofilm and growth inhibition in P. aeruginosa (PAO1). Compound 6b displayed the highest pqs inhibitory activity (73.4%, 72.1% and 53.7% at 100, 50 and 25 µM, respectively) with no bacterial growth inhibition. However, compounds 6b and 6e only inhibited biofilm formation by 10% and 5%, respectively. Full article
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25 pages, 1987 KiB  
Article
Investigation of Naphthyl–Polyamine Conjugates as Antimicrobials and Antibiotic Enhancers
by Melissa M. Cadelis, Liam R. Edmeades, Dan Chen, Evangelene S. Gill, Kyle Fraser, Florent Rouvier, Marie-Lise Bourguet-Kondracki, Jean Michel Brunel and Brent R. Copp
Antibiotics 2023, 12(6), 1014; https://doi.org/10.3390/antibiotics12061014 - 5 Jun 2023
Cited by 1 | Viewed by 1584
Abstract
As part of our search for new antimicrobials and antibiotic enhancers, a series of naphthyl- and biphenyl-substituted polyamine conjugates have been synthesized. The structurally-diverse library of compounds incorporated variation in the capping end groups and in the length of the polyamine (PA) core. [...] Read more.
As part of our search for new antimicrobials and antibiotic enhancers, a series of naphthyl- and biphenyl-substituted polyamine conjugates have been synthesized. The structurally-diverse library of compounds incorporated variation in the capping end groups and in the length of the polyamine (PA) core. Longer chain (PA-3-12-3) variants containing both 1-naphthyl and 2-naphthyl capping groups exhibited more pronounced intrinsic antimicrobial properties against methicillin-resistant Staphylococcus aureus (MRSA) (MIC ≤ 0.29 µM) and the fungus Cryptococcus neoformans (MIC ≤ 0.29 µM). Closer mechanistic study of one of these analogues, 20f, identified it as a bactericide. In contrast to previously reported diarylacyl-substituted polyamines, several examples in the current set were able to enhance the antibiotic action of doxycycline and/or erythromycin towards the Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli. Two analogues (19a and 20c) were of note, exhibiting greater than 32-fold enhancement in activity. This latter result suggests that α,ω-disubstituted polyamines bearing 1-naphthyl- and 2-naphthyl-capping groups are worthy of further investigation and optimization as non-toxic antibiotic enhancers. Full article
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15 pages, 3413 KiB  
Article
Exploring Alternative Pathways to Target Bacterial Type II Topoisomerases Using NBTI Antibacterials: Beyond Halogen-Bonding Interactions
by Maja Kokot, Doroteja Novak, Irena Zdovc, Marko Anderluh, Martina Hrast and Nikola Minovski
Antibiotics 2023, 12(5), 930; https://doi.org/10.3390/antibiotics12050930 - 18 May 2023
Cited by 3 | Viewed by 1525
Abstract
Novel bacterial topoisomerase inhibitors (NBTIs) are a new class of antibacterial agents that target bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). Our recently disclosed crystal structure of an NBTI ligand in complex with DNA gyrase and DNA revealed that the halogen [...] Read more.
Novel bacterial topoisomerase inhibitors (NBTIs) are a new class of antibacterial agents that target bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). Our recently disclosed crystal structure of an NBTI ligand in complex with DNA gyrase and DNA revealed that the halogen atom in the para position of the phenyl right hand side (RHS) moiety is able to establish strong symmetrical bifurcated halogen bonds with the enzyme; these are responsible for the excellent enzyme inhibitory potency and antibacterial activity of these NBTIs. To further assess the possibility of any alternative interactions (e.g., hydrogen-bonding and/or hydrophobic interactions), we introduced various non-halogen groups at the p-position of the phenyl RHS moiety. Considering the hydrophobic nature of amino acid residues delineating the NBTI’s binding pocket in bacterial topoisomerases, we demonstrated that designed NBTIs cannot establish any hydrogen-bonding interactions with the enzyme; hydrophobic interactions are feasible in all respects, while halogen-bonding interactions are apparently the most preferred. Full article
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17 pages, 4389 KiB  
Article
Employing Gamma-Ray-Modified Carbon Quantum Dots to Combat a Wide Range of Bacteria
by Zoran M. Marković, Aleksandra S. Mišović, Danica Z. Zmejkoski, Nemanja M. Zdravković, Janez Kovač, Danica V. Bajuk-Bogdanović, Dušan D. Milivojević, Marija M. Mojsin, Milena J. Stevanović, Vladimir B. Pavlović and Biljana M. Todorović Marković
Antibiotics 2023, 12(5), 919; https://doi.org/10.3390/antibiotics12050919 - 17 May 2023
Cited by 3 | Viewed by 2443
Abstract
Nowadays, it is a great challenge to develop new medicines for treating various infectious diseases. The treatment of these diseases is of utmost interest to further prevent the development of multi-drug resistance in different pathogens. Carbon quantum dots, as a new member of [...] Read more.
Nowadays, it is a great challenge to develop new medicines for treating various infectious diseases. The treatment of these diseases is of utmost interest to further prevent the development of multi-drug resistance in different pathogens. Carbon quantum dots, as a new member of the carbon nanomaterials family, can potentially be used as a highly promising visible-light-triggered antibacterial agent. In this work, the results of antibacterial and cytotoxic activities of gamma-ray-irradiated carbon quantum dots are presented. Carbon quantum dots (CQDs) were synthesized from citric acid by a pyrolysis procedure and irradiated by gamma rays at different doses (25, 50, 100 and 200 kGy). Structure, chemical composition and optical properties were investigated by atomic force microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, Raman spectroscopy, UV-Vis spectrometry and photoluminescence. Structural analysis showed that CQDs have a spherical-like shape and dose-dependent average diameters and heights. Antibacterial tests showed that all irradiated dots had antibacterial activity but CQDs irradiated with dose of 100 kGy had antibacterial activity against all seven pathogen-reference bacterial strains. Gamma-ray-modified CQDs did not show any cytotoxicity toward human fetal-originated MRC-5 cells. Moreover, fluorescence microscopy showed excellent cellular uptake of CQDs irradiated with doses of 25 and 200 kGy into MRC-5 cells. Full article
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20 pages, 3726 KiB  
Article
Harnessing the Dual Antimicrobial Mechanism of Action with Fe(8-Hydroxyquinoline)3 to Develop a Topical Ointment for Mupirocin-Resistant MRSA Infections
by Nalin Abeydeera, Bogdan M. Benin, Khalil Mudarmah, Bishnu D. Pant, Guanyu Chen, Woo Shik Shin, Min-Ho Kim and Songping D. Huang
Antibiotics 2023, 12(5), 886; https://doi.org/10.3390/antibiotics12050886 - 10 May 2023
Cited by 2 | Viewed by 1957
Abstract
8-Hydroxyquinoline (8-hq) exhibits potent antimicrobial activity against Staphylococcus aureus (SA) bacteria with MIC = 16.0–32.0 µM owing to its ability to chelate metal ions such as Mn2+, Zn2+, and Cu2+ to disrupt metal homeostasis in bacterial cells. We demonstrate [...] Read more.
8-Hydroxyquinoline (8-hq) exhibits potent antimicrobial activity against Staphylococcus aureus (SA) bacteria with MIC = 16.0–32.0 µM owing to its ability to chelate metal ions such as Mn2+, Zn2+, and Cu2+ to disrupt metal homeostasis in bacterial cells. We demonstrate that Fe(8-hq)3, the 1:3 complex formed between Fe(III) and 8-hq, can readily transport Fe(III) across the bacterial cell membrane and deliver iron into the bacterial cell, thus, harnessing a dual antimicrobial mechanism of action that combines the bactericidal activity of iron with the metal chelating effect of 8-hq to kill bacteria. As a result, the antimicrobial potency of Fe(8-hq)3 is significantly enhanced in comparison with 8-hq. Resistance development by SA toward Fe(8-hq)3 is considerably delayed as compared with ciprofloxacin and 8-hq. Fe(8-hq)3 can also overcome the 8-hq and mupirocin resistance developed in the SA mutant and MRSA mutant bacteria, respectively. Fe(8-hq)3 can stimulate M1-like macrophage polarization of RAW 264.7 cells to kill the SA internalized in such macrophages. Fe(8-hq)3 exhibits a synergistic effect with both ciprofloxacin and imipenem, showing potential for combination therapies with topical and systemic antibiotics for more serious MRSA infections. The in vivo antimicrobial efficacy of a 2% Fe(8-hq)3 topical ointment is confirmed by the use of a murine model with skin wound infection by bioluminescent SA with a reduction of the bacterial burden by 99 ± 0.5%, indicating that this non-antibiotic iron complex has therapeutic potential for skin and soft tissue infections (SSTIs). Full article
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16 pages, 1951 KiB  
Article
Pseudomonas aeruginosa and Staphylococcus aureus Display Differential Proteomic Responses to the Silver(I) Compound, SBC3
by Magdalena Piatek, Cillian O’Beirne, Zoe Beato, Matthias Tacke and Kevin Kavanagh
Antibiotics 2023, 12(2), 348; https://doi.org/10.3390/antibiotics12020348 - 8 Feb 2023
Cited by 5 | Viewed by 2920
Abstract
The urgent need to combat antibiotic resistance and develop novel antimicrobial therapies has triggered studies on novel metal-based formulations. N-heterocyclic carbene (NHC) complexes coordinate transition metals to generate a broad range of anticancer and/or antimicrobial agents, with ongoing efforts being made to [...] Read more.
The urgent need to combat antibiotic resistance and develop novel antimicrobial therapies has triggered studies on novel metal-based formulations. N-heterocyclic carbene (NHC) complexes coordinate transition metals to generate a broad range of anticancer and/or antimicrobial agents, with ongoing efforts being made to enhance the lipophilicity and drug stability. The lead silver(I) acetate complex, 1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene (NHC*) (SBC3), has previously demonstrated promising growth and biofilm-inhibiting properties. In this work, the responses of two structurally different bacteria to SBC3 using label-free quantitative proteomics were characterised. Multidrug-resistant Pseudomonas aeruginosa (Gram-negative) and Staphylococcus aureus (Gram-positive) are associated with cystic fibrosis lung colonisation and chronic wound infections, respectively. SBC3 increased the abundance of alginate biosynthesis, the secretion system and drug detoxification proteins in P. aeruginosa, whilst a variety of pathways, including anaerobic respiration, twitching motility and ABC transport, were decreased in abundance. This contrasted the affected pathways in S. aureus, where increased DNA replication/repair and cell redox homeostasis and decreased protein synthesis, lipoylation and glucose metabolism were observed. Increased abundance of cell wall/membrane proteins was indicative of the structural damage induced by SBC3 in both bacteria. These findings show the potential broad applications of SBC3 in treating Gram-positive and Gram-negative bacteria. Full article
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Review

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22 pages, 1688 KiB  
Review
Using Subcritical Water to Obtain Polyphenol-Rich Extracts with Antimicrobial Properties
by Tjaša Žagar, Rok Frlan and Nina Kočevar Glavač
Antibiotics 2024, 13(4), 334; https://doi.org/10.3390/antibiotics13040334 - 5 Apr 2024
Viewed by 747
Abstract
The use of green extraction methods that meet the criteria of sustainable and environmentally friendly technologies has been increasing in recent decades due to their many benefits. In this respect, extracts obtained using subcritical water are also gaining increased attention because of their [...] Read more.
The use of green extraction methods that meet the criteria of sustainable and environmentally friendly technologies has been increasing in recent decades due to their many benefits. In this respect, extracts obtained using subcritical water are also gaining increased attention because of their potential antioxidant and antimicrobial properties. Their antimicrobial activity is mainly due to the presence of various polyphenolic compounds. Although the exact mechanism of the antibacterial action of polyphenolic compounds has not yet been fully investigated and described, polyphenols are known to affect the bacterial cell at several cellular levels; among other things, they cause changes and ruptures in the cell membranes of the bacterial cell, affect the inactivation of bacterial enzymes and damage bacterial DNA. The difference in the strength of the antimicrobial activity of the extracts is most likely a result of differences in their lipophilicity and in the number and position of hydroxyl groups and double bonds in the chemical structure of polyphenols. By changing the extraction conditions, especially the temperature, during subcritical water extraction, we affect the solubility of the compounds we want to extract. In general, as the temperature increases, the solubility of polyphenolic compounds also increases, and the reduction of the surface tension of subcritical water at higher temperatures also enables faster dissolution of polyphenolic compounds. Different bacterial strains have different sensitivity to different extracts. However, extracts obtained with subcritical water extraction demonstrate strong antimicrobial activity compared to extracts obtained with conventional methods. Full article
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20 pages, 336 KiB  
Review
A Review of the Clinical Utilization of Oral Antibacterial Therapy in the Treatment of Bone Infections in Adults
by Nicholas Haddad, Jibran Ajaz, Lina Mansour, Robert Kasemodel, Jennifer Jarvis, John Jarad, Haley Gorski and Maddie Carr
Antibiotics 2024, 13(1), 4; https://doi.org/10.3390/antibiotics13010004 - 19 Dec 2023
Viewed by 2412
Abstract
Chronic osteomyelitis in adults is managed with prolonged courses of intravenous antibiotics in conjunction with surgical debridement of necrotic bone. Over the past 40 years, there has been no paradigm shift in this approach, as randomized controlled trials of this standard of care [...] Read more.
Chronic osteomyelitis in adults is managed with prolonged courses of intravenous antibiotics in conjunction with surgical debridement of necrotic bone. Over the past 40 years, there has been no paradigm shift in this approach, as randomized controlled trials of this standard of care compared to alternatives such as prolonged oral antibiotics are scarce. However, there have been many small trials, case reports, and review papers evaluating the effectiveness of oral treatment for chronic osteomyelitis. The oral route for infections requiring prolonged treatment is intuitively and practically more favorable due to several advantages, the most important of which is the avoidance of long-term IV antimicrobial therapy with its complications, inconvenience, and cost. In this paper, we review the literature evaluating oral antibiotic therapy in the management of chronic bone infections since 1975. The majority of osteomyelitis infections are caused by Staphylococcus aureus, hence we focus on its treatment using oral antibiotics; however, we also emphasize subpopulations of patients with diabetes, implanted hardware, and with less common bacterial organisms. The primary objective of this review is to promulgate clinical recommendations on the use of oral antibiotics in bone infections in the context of initial therapy, transition from intravenous therapy, and the role of chronic suppression. The secondary objective is to summarize current knowledge of the specific oral antimicrobial agents that are commonly utilized, together with a synopsis of the available literature pertaining to their pharmacokinetic/pharmacodynamic properties and duration of therapy in bone infection. Full article
36 pages, 24719 KiB  
Review
A Comprehensive Review on Chemical Synthesis and Chemotherapeutic Potential of 3-Heteroaryl Fluoroquinolone Hybrids
by Halyna Hryhoriv, Sergiy M. Kovalenko, Marine Georgiyants, Lyudmila Sidorenko and Victoriya Georgiyants
Antibiotics 2023, 12(3), 625; https://doi.org/10.3390/antibiotics12030625 - 21 Mar 2023
Cited by 4 | Viewed by 2376
Abstract
Fluoroquinolones have been studied for more than half a century. Since the 1960s, four generations of these synthetic antibiotics have been created and successfully introduced into clinical practice. However, they are still of interest for medicinal chemistry due to the wide possibilities for [...] Read more.
Fluoroquinolones have been studied for more than half a century. Since the 1960s, four generations of these synthetic antibiotics have been created and successfully introduced into clinical practice. However, they are still of interest for medicinal chemistry due to the wide possibilities for chemical modification, with subsequent useful changes in the pharmacokinetics and pharmacodynamics of the initial molecules. This review summarizes the chemical and pharmacological results of fluoroquinolones hybridization by introducing different heterocyclic moieties into position 3 of the core system. It analyses the synthetic procedures and approaches to the formation of heterocycles from the fluoroquinolone carboxyl group and reveals the most convenient ways for such procedures. Further, the results of biological activity investigations for the obtained hybrid pharmacophore systems are presented. The latter revealed numerous promising molecules that can be further studied to overcome the problem of resistance to antibiotics, to find novel anticancer agents and more. Full article
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