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Bioorganic Chemistry Nov 2020Replication proteins are sought as a potential targets for antimicrobial agents. Despite their promising target characteristics, only topoisomerase II inhibitors... (Review)
Review
Replication proteins are sought as a potential targets for antimicrobial agents. Despite their promising target characteristics, only topoisomerase II inhibitors targeting DNA gyrase and/or topoisomerase IV have reached clinical use. Topoisomerases are the enzymes that are essential for cellular functions and various biological activities. A wide range of natural and synthetic compounds have been identified as potential topoisomerase inhibitors but the resistance is most commonly found in these drugs. The emergence of FQ resistance has increased the need for the development of novel topoisomerase inhibitors with efficacy and high potency against FQ-resistant strains. Besides structural modifications of existing FQ scaffolds, novel non-quinolone topoisomerase II inhibitors, known as novel bacterial topoisomerase inhibitors, have been developed which showed remarkable inhibitory activity against DNA gyrase/topoisomerase IV or both with an improved spectrum of antibacterial potency including drug-resistant strains. This review aims to summarize various recent advancements in the medicinal chemistry of topoisomerase inhibitors with the following objectives: (1) To represent inclusive data on types of topoisomerases and various marketed topoisomerase inhibitors as drugs; (2) To discuss the recent advances in the medicinal chemistry of various topoisomerase inhibitors (DNA gyrase and topo IV) belonging to different structural classes as potential antibacterial agents; (3) To summarizes the structure activity relationship (SAR) including in silico and mechanistic studies to afford ideas and to provide focused direction for the development of new chemical entities which are effective against drug-resistant bacterial pathogens and biofilms.
Topics: Anti-Bacterial Agents; Chemistry, Pharmaceutical; DNA Topoisomerases, Type II; Dose-Response Relationship, Drug; Molecular Structure; Structure-Activity Relationship; Topoisomerase II Inhibitors
PubMed: 33142421
DOI: 10.1016/j.bioorg.2020.104266 -
Future Medicinal Chemistry Dec 2021
Topics: Anti-Bacterial Agents; DNA Gyrase; Drug Discovery; Humans; Topoisomerase Inhibitors
PubMed: 34605249
DOI: 10.4155/fmc-2021-0266 -
Molecular Microbiology Jan 2023Transcription is a noisy and stochastic process that produces sibling-to-sibling variations in physiology across a population of genetically identical cells. This... (Review)
Review
Transcription is a noisy and stochastic process that produces sibling-to-sibling variations in physiology across a population of genetically identical cells. This pattern of diversity reflects, in part, the burst-like nature of transcription. Transcription bursting has many causes and a failure to remove the supercoils that accumulate in DNA during transcription elongation is an important contributor. Positive supercoiling of the DNA ahead of the transcription elongation complex can result in RNA polymerase stalling if this DNA topological roadblock is not removed. The relaxation of these positive supercoils is performed by the ATP-dependent type II topoisomerases DNA gyrase and topoisomerase IV. Interference with the action of these topoisomerases involving, inter alia, topoisomerase poisons, fluctuations in the [ATP]/[ADP] ratio, and/or the intervention of nucleoid-associated proteins with GapR-like or YejK-like activities, may have consequences for the smooth operation of the transcriptional machinery. Antibiotic-tolerant (but not resistant) persister cells are among the phenotypic outliers that may emerge. However, interference with type II topoisomerase activity can have much broader consequences, making it an important epigenetic driver of physiological diversity in the bacterial population.
Topics: DNA; DNA Gyrase; DNA Topoisomerase IV; Bacteria; DNA Topoisomerases, Type I; Adenosine Triphosphate; Epigenesis, Genetic; DNA, Superhelical; DNA, Bacterial
PubMed: 36565252
DOI: 10.1111/mmi.15014 -
The Journal of Antimicrobial... Oct 2020To evaluate the efficacy of two novel compounds against mycobacteria and determine the molecular basis of their action on DNA gyrase using structural and mechanistic...
OBJECTIVES
To evaluate the efficacy of two novel compounds against mycobacteria and determine the molecular basis of their action on DNA gyrase using structural and mechanistic approaches.
METHODS
Redx03863 and Redx04739 were tested in antibacterial assays, and also against their target, DNA gyrase, using DNA supercoiling and ATPase assays. X-ray crystallography was used to determine the structure of the gyrase B protein ATPase sub-domain from Mycobacterium smegmatis complexed with the aminocoumarin drug novobiocin, and structures of the same domain from Mycobacterium thermoresistibile complexed with novobiocin, and also with Redx03863.
RESULTS
Both compounds, Redx03863 and Redx04739, were active against selected Gram-positive and Gram-negative species, with Redx03863 being the more potent, and Redx04739 showing selectivity against M. smegmatis. Both compounds were potent inhibitors of the supercoiling and ATPase reactions of DNA gyrase, but did not appreciably affect the ATP-independent relaxation reaction. The structure of Redx03863 bound to the gyrase B protein ATPase sub-domain from M. thermoresistibile shows that it binds at a site adjacent to the ATP- and novobiocin-binding sites. We found that most of the mutations that we made in the Redx03863-binding pocket, based on the structure, rendered gyrase inactive.
CONCLUSIONS
Redx03863 and Redx04739 inhibit gyrase by preventing the binding of ATP. The fact that the Redx03863-binding pocket is distinct from that of novobiocin, coupled with the lack of activity of resistant mutants, suggests that such compounds could have potential to be further exploited as antibiotics.
Topics: Adenosine Triphosphatases; DNA Gyrase; Mycobacteriaceae; Mycobacterium; Novobiocin; Topoisomerase II Inhibitors
PubMed: 32728686
DOI: 10.1093/jac/dkaa286 -
Clinical Microbiology and Infection :... Nov 2021The fact that Mycobacterium leprae does not grow in vitro remains a challenge in the survey of its antimicrobial resistance (AMR). Mainly molecular methods are used to... (Review)
Review
BACKGROUND
The fact that Mycobacterium leprae does not grow in vitro remains a challenge in the survey of its antimicrobial resistance (AMR). Mainly molecular methods are used to diagnose AMR in M. leprae to provide reliable data concerning mutations and their impact. Fluoroquinolones (FQs) are efficient for the treatment of leprosy and the main second-line drugs in case of multidrug resistance.
OBJECTIVES
This study aimed at performing a systematic review (a) to characterize all DNA gyrase gene mutations described in clinical isolates of M. leprae, (b) to distinguish between those associated with FQ resistance or susceptibility and (c) to delineate a consensus numbering system for M. leprae GyrA and GyrB.
DATA SOURCES
Data source was PubMed.
STUDY ELIGIBILITY CRITERIA
Publications reporting genotypic susceptibility-testing methods and gyrase gene mutations in M. leprae clinical strains.
RESULTS
In 25 studies meeting our inclusion criteria, 2884 M. leprae isolates were analysed (2236 for gyrA only (77%) and 755 for both gyrA and gyrB (26%)): 3.8% of isolates had gyrA mutations (n = 110), mostly at position 91 (n = 75, 68%) and 0.8% gyrB mutations (n = 6). Since we found discrepancies regarding the location of substitutions associated with FQ resistance, we established a consensus numbering system to properly number the mutations. We also designed a 3D model of the M. leprae DNA gyrase to predict the impact of mutations whose role in FQ-susceptibility has not been demonstrated previously.
CONCLUSIONS
Mutations in DNA gyrase are observed in 4% of the M. leprae clinical isolates. To solve discrepancies among publications and to distinguish between mutations associated with FQ resistance or susceptibility, the consensus numbering system we proposed as well as the 3D model of the M. leprae gyrase for the evaluation of the impact of unknown mutations in FQ resistance, will provide help for resistance surveillance.
Topics: DNA Gyrase; Drug Resistance, Bacterial; Fluoroquinolones; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium leprae
PubMed: 34265461
DOI: 10.1016/j.cmi.2021.07.007 -
European Journal of Medicinal Chemistry Apr 2021Compounds incorporating guanidine moieties constitute a versatile class of biologically interesting molecules with a wide array of applications. As such, guanidines have... (Review)
Review
Compounds incorporating guanidine moieties constitute a versatile class of biologically interesting molecules with a wide array of applications. As such, guanidines have been exploited as privileged structural motifs in designing novel drugs for the treatment of various infectious and non-infectious diseases. In designing anti-infective agents, this moiety carries great appeal by virtue of attributes such as hydrogen-bonding capability and protonatability at physiological pH in the context of interaction with biological targets. This review provides an overview of recent advances in hit-to-lead development studies of antimicrobial guanidine-containing compounds with the aim to highlight their structural diversity and the pharmacological relevance of the moiety to drug activity, insofar as possible. In so doing, emphasis is put on chemical and microbiological properties of such compounds in relation to antibacterial, antifungal and antimalarial activities.
Topics: Anti-Infective Agents; Binding Sites; DNA Gyrase; Drug Design; Fungi; Gram-Positive Bacteria; Guanidine; Microbial Sensitivity Tests; Molecular Dynamics Simulation; Structure-Activity Relationship
PubMed: 33640673
DOI: 10.1016/j.ejmech.2021.113293 -
The Journal of Antimicrobial... Aug 2023Fluoroquinolones (FQs) are potent and broad-spectrum antibiotics commonly used to treat MDR bacterial infections, but bacterial resistance to FQs has emerged and spread...
BACKGROUND
Fluoroquinolones (FQs) are potent and broad-spectrum antibiotics commonly used to treat MDR bacterial infections, but bacterial resistance to FQs has emerged and spread rapidly around the world. The mechanisms for FQ resistance have been revealed, including one or more mutations in FQ target genes such as DNA gyrase (gyrA) and topoisomerase IV (parC). Because therapeutic treatments for FQ-resistant bacterial infections are limited, it is necessary to develop novel antibiotic alternatives to minimize or inhibit FQ-resistant bacteria.
OBJECTIVES
To examine the bactericidal effect of antisense peptide-peptide nucleic acids (P-PNAs) that can block the expression of DNA gyrase or topoisomerase IV in FQ-resistant Escherichia coli (FRE).
METHODS
A set of antisense P-PNA conjugates with a bacterial penetration peptide were designed to inhibit the expression of gyrA and parC and were evaluated for their antibacterial activities.
RESULTS
Antisense P-PNAs, ASP-gyrA1 and ASP-parC1, targeting the translational initiation sites of their respective target genes significantly inhibited the growth of the FRE isolates. In addition, ASP-gyrA3 and ASP-parC2, which bind to the FRE-specific coding sequence within the gyrA and parC structural genes, respectively, showed selective bactericidal effects against FRE isolates.
CONCLUSIONS
Our results demonstrate the potential of targeted antisense P-PNAs as antibiotic alternatives against FQ-resistance bacteria.
Topics: Fluoroquinolones; Escherichia coli; Peptide Nucleic Acids; DNA Gyrase; DNA Topoisomerase IV; Anti-Bacterial Agents; Bacteria; Mutation; Microbial Sensitivity Tests; Drug Resistance, Bacterial
PubMed: 37390375
DOI: 10.1093/jac/dkad203 -
Current Medicinal Chemistry 2021In the past few decades, with the abuse of antibiotics, bacterial resistance has enhanced constantly. More and more super species of bacteria, which are seriously... (Review)
Review
BACKGROUND
In the past few decades, with the abuse of antibiotics, bacterial resistance has enhanced constantly. More and more super species of bacteria, which are seriously threatening human health, have been discovered. Developing novel antibacterial agents to overcome the drug-resistance is an urgent duty. We all know that blocking the information-transfer of bacterial DNA and RNA is one of the effective ways to inhibit bacterial growth. Therefore, as the indispensable enzyme for DNA replication and transcription, DNA gyrase is one of the important targets for bacterial inhibitors. Accordingly, many inhibitors of DNA gyrase have also been developed.
METHODS
In this review, to highlight the recent progress in DNA gyrase inhibitors, the study in this field over the past three years (2017-2019) was summarized and organized based on their backbones or core moieties. Both of the subunits of DNA gyrase were taken into consideration.
RESULTS
These DNA gyrase inhibitors have been classified based on their backbones or core moieties. After the comparison of the divided 14 categories, we could achieve some clues for future modification. In particular, we found that benzodiazepines and naphthalene heterocycles were the most common structures in the drug design. On the other hand, isopropyl and cyclopropyl have also been used in drug design, which provides more inspiration for the investigations. Except for GSK2140944, which has entered the phase III clinical trial stage, other compounds here were not fully promulgated with their optimal pharmacokinetic activity.
CONCLUSION
We briefly summed up the current situation and future challenges on this topic. Through the discussion of the design strategies and drug effect, we hope that this review can provide a focused direction for future researches.
Topics: Anti-Bacterial Agents; Bacteria; DNA Gyrase; DNA, Bacterial; Humans; Microbial Sensitivity Tests; Topoisomerase II Inhibitors
PubMed: 33530900
DOI: 10.2174/1871529X21666210202113128 -
Molecules (Basel, Switzerland) Nov 2021Broad antibacterial spectrum, high oral bioavailability and excellent tissue penetration combined with safety and few, yet rare, unwanted effects, have made the... (Review)
Review
Broad antibacterial spectrum, high oral bioavailability and excellent tissue penetration combined with safety and few, yet rare, unwanted effects, have made the quinolones class of antimicrobials one of the most used in inpatients and outpatients. Initially discovered during the search for improved chloroquine-derivative molecules with increased anti-malarial activity, today the quinolones, intended as antimicrobials, comprehend four generations that progressively have been extending antimicrobial spectrum and clinical use. The quinolone class of antimicrobials exerts its antimicrobial actions through inhibiting DNA gyrase and Topoisomerase IV that in turn inhibits synthesis of DNA and RNA. Good distribution through different tissues and organs to treat Gram-positive and Gram-negative bacteria have made quinolones a good choice to treat disease in both humans and animals. The extensive use of quinolones, in both human health and in the veterinary field, has induced a rise of resistance and menace with leaving the quinolones family ineffective to treat infections. This review revises the evolution of quinolones structures, biological activity, and the clinical importance of this evolving family. Next, updated information regarding the mechanism of antimicrobial activity is revised. The veterinary use of quinolones in animal productions is also considered for its environmental role in spreading resistance. Finally, considerations for the use of quinolones in human and veterinary medicine are discussed.
Topics: Anti-Infective Agents; Bacterial Infections; DNA Gyrase; DNA Topoisomerase IV; DNA, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Quinolones; RNA, Bacterial; Topoisomerase II Inhibitors
PubMed: 34885734
DOI: 10.3390/molecules26237153 -
Archiv Der Pharmazie Feb 2021Herein, we report the synthesis and in vitro antimicrobial evaluation of novel quinoline derivatives as DNA gyrase inhibitors. The preliminary antimicrobial activity was...
Herein, we report the synthesis and in vitro antimicrobial evaluation of novel quinoline derivatives as DNA gyrase inhibitors. The preliminary antimicrobial activity was assessed against a panel of pathogenic microbes including Gram-positive bacteria (Streptococcus pneumoniae and Bacillus subtilis), Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), and fungal strains (Aspergillus fumigatus, Syncephalastrum racemosum, Geotrichum candidum, and Candida albicans). Compounds that revealed the best activity were subjected to further biological studies to determine their minimum inhibitory concentrations (MICs) against the selected pathogens as well as their in vitro activity against the E. coli DNA gyrase, to realize whether their antimicrobial action is mediated via inhibition of this enzyme. Four of the new derivatives (14, 17, 20, and 23) demonstrated a relatively potent antimicrobial activity with MIC values in the range of 0.66-5.29 μg/ml. Among them, compound 14 exhibited a particularly potent broad-spectrum antimicrobial activity against most of the tested strains of bacteria and fungi, with MIC values in the range of 0.66-3.98 μg/ml. A subsequent in vitro investigation against the bacterial DNA gyrase target enzyme revealed a significant potent inhibitory activity of quinoline derivative 14, which can be observed from its IC value (3.39 μM). Also, a molecular docking study of the most active compounds was carried out to explore the binding affinity of the new ligands toward the active site of DNA gyrase enzyme as a proposed target of their activity. Furthermore, the ADMET profiles of the most highly effective derivatives were analyzed to evaluate their potentials to be developed as good drug candidates.
Topics: Anti-Bacterial Agents; Antifungal Agents; DNA Gyrase; Dose-Response Relationship, Drug; Fungi; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Microbial Sensitivity Tests; Molecular Structure; Quinolines; Structure-Activity Relationship; Topoisomerase II Inhibitors
PubMed: 33078877
DOI: 10.1002/ardp.202000277