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Expert Opinion on Therapeutic Patents Mar 2019The bacterial topoisomerases DNA gyrase and topoisomerase IV are validated targets for development of novel antibacterial agents. Fluoroquinolones inhibit the catalytic... (Review)
Review
INTRODUCTION
The bacterial topoisomerases DNA gyrase and topoisomerase IV are validated targets for development of novel antibacterial agents. Fluoroquinolones inhibit the catalytic GyrA and/or ParC(GrlA) subunit and have been commonly used, although these have toxicity liabilities that restrict their use. The ATPase GyrB and ParE(GrlB) subunits have been much less explored and after withdrawal of novobiocin, there are no further marketed inhibitors . ATP-competitive inhibitors of GyrB and/or ParE(GrlB) are of special interest, as this target has been validated, and it is expected that many of the problems associated with fluoroquinolones can be avoided.
AREAS COVERED
This review summarises the development of ATP-competitive inhibitors of GyrB and/or ParE(GrlB) as novel antibacterial agents over the last 10 years. Structural features of the new inhibitors and their optimisation strategies are highlighted.
EXPERT OPINION
The development of novel ATP-competitive inhibitors of GyrB and/or ParE(GrlB) is ongoing in industrial and academical research. Development of resistance is one of the most problematic issues, but GyrB/ParE(GrlB) inhibitors do not show cross-resistance with fluoroquinolones. Other common issues, such as low solubility, high protein binding, development of off-target resistance, are related to the structures of the inhibitors themselves, which is thus a main focus of design strategies. With some now in early clinical development, there is reasonable expectation that novel ATP-competitive inhibitors of GyrB/ParE(GrlB) will reach the market in the near future.
Topics: Adenosine Triphosphate; Animals; Anti-Bacterial Agents; DNA Gyrase; DNA Topoisomerase IV; Drug Design; Fluoroquinolones; Humans; Patents as Topic; Topoisomerase II Inhibitors
PubMed: 30686070
DOI: 10.1080/13543776.2019.1575362 -
Annals of the New York Academy of... Sep 2015Quinolone antimicrobials are synthetic and widely used in clinical medicine. Resistance emerged with clinical use and became common in some bacterial pathogens.... (Review)
Review
Quinolone antimicrobials are synthetic and widely used in clinical medicine. Resistance emerged with clinical use and became common in some bacterial pathogens. Mechanisms of resistance include two categories of mutation and acquisition of resistance-conferring genes. Resistance mutations in one or both of the two drug target enzymes, DNA gyrase and DNA topoisomerase IV, are commonly in a localized domain of the GyrA and ParE subunits of the respective enzymes and reduce drug binding to the enzyme-DNA complex. Other resistance mutations occur in regulatory genes that control the expression of native efflux pumps localized in the bacterial membrane(s). These pumps have broad substrate profiles that include quinolones as well as other antimicrobials, disinfectants, and dyes. Mutations of both types can accumulate with selection pressure and produce highly resistant strains. Resistance genes acquired on plasmids can confer low-level resistance that promotes the selection of mutational high-level resistance. Plasmid-encoded resistance is due to Qnr proteins that protect the target enzymes from quinolone action, one mutant aminoglycoside-modifying enzyme that also modifies certain quinolones, and mobile efflux pumps. Plasmids with these mechanisms often encode additional antimicrobial resistances and can transfer multidrug resistance that includes quinolones. Thus, the bacterial quinolone resistance armamentarium is large.
Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Bacterial Proteins; DNA Gyrase; DNA Topoisomerase IV; Drug Resistance, Bacterial; Humans; Mutation; Quinolones
PubMed: 26190223
DOI: 10.1111/nyas.12830 -
Nucleic Acids Research Jun 2021Type IIA topoisomerases catalyze a variety of different reactions: eukaryotic topoisomerase II relaxes DNA in an ATP-dependent reaction, whereas the bacterial... (Review)
Review
Type IIA topoisomerases catalyze a variety of different reactions: eukaryotic topoisomerase II relaxes DNA in an ATP-dependent reaction, whereas the bacterial representatives gyrase and topoisomerase IV (Topo IV) preferentially introduce negative supercoils into DNA (gyrase) or decatenate DNA (Topo IV). Gyrase and Topo IV perform separate, dedicated tasks during replication: gyrase removes positive supercoils in front, Topo IV removes pre-catenanes behind the replication fork. Despite their well-separated cellular functions, gyrase and Topo IV have an overlapping activity spectrum: gyrase is also able to catalyze DNA decatenation, although less efficiently than Topo IV. The balance between supercoiling and decatenation activities is different for gyrases from different organisms. Both enzymes consist of a conserved topoisomerase core and structurally divergent C-terminal domains (CTDs). Deletion of the entire CTD, mutation of a conserved motif and even by just a single point mutation within the CTD converts gyrase into a Topo IV-like enzyme, implicating the CTDs as the major determinant for function. Here, we summarize the structural and mechanistic features that make a type IIA topoisomerase a gyrase or a Topo IV, and discuss the implications for type IIA topoisomerase evolution.
Topics: Bacteria; DNA; DNA Gyrase; DNA Topoisomerase IV; DNA Topoisomerases, Type II; Evolution, Molecular; Protein Conformation; Protein Domains
PubMed: 33905522
DOI: 10.1093/nar/gkab270 -
Mini Reviews in Medicinal Chemistry 2024Antibiotic or antimicrobial resistance is an urgent global public health threat that occurs when bacterial or fungal infections do not respond to the drug regimen... (Review)
Review
Antibiotic or antimicrobial resistance is an urgent global public health threat that occurs when bacterial or fungal infections do not respond to the drug regimen designed to treat these infections. As a result, these microbes are not evaded and continue to grow. Antibiotic resistance against natural and already-known antibiotics like Ciprofloxacin and Novobiocin can be overcome by developing an agent that can act in different ways. The success of agents like Zodiflodacin and Zenoxacin in clinical trials against DNA gyrase inhibitors that act on different sites of DNA gyrase has resulted in further exploration of this target. However, due to the emergence of bacterial resistance against these targets, there is a great need to design agents that can overcome this resistance and act with greater efficacy. This review provides information on the synthetic and natural DNA gyrase inhibitors that have been developed recently and their promising potential for combating antimicrobial resistance. The review also presents information on molecules that are in clinical trials and their current status. It also analysed the SAR studies and mechanisms of action of enlisted agents.
Topics: Topoisomerase II Inhibitors; DNA Gyrase; Humans; Anti-Bacterial Agents; Bacteria; Microbial Sensitivity Tests; Structure-Activity Relationship
PubMed: 37909434
DOI: 10.2174/0113895575264264230921080718 -
Future Medicinal Chemistry Mar 2022Bacterial resistance to antibiotics threatens our progress in healthcare, modern medicine, food production and ultimately life expectancy. Antibiotic resistance is a... (Review)
Review
Bacterial resistance to antibiotics threatens our progress in healthcare, modern medicine, food production and ultimately life expectancy. Antibiotic resistance is a global concern, which spreads rapidly across borders and continents due to rapid travel of people, animals and goods. Derivatives of metabolically stable pyrazole nucleus are known for their wide range of pharmacological properties, including antibacterial activities. This review highlights recent reports of pyrazole derivatives targeting different bacterial strains focusing on the drug-resistant variants. Pyrazole derivatives target different metabolic pathways of both Gram-positive and Gram-negative bacteria.
Topics: Alkyl and Aryl Transferases; Anti-Bacterial Agents; Cell Wall; DNA Gyrase; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Pyrazoles; Tetrahydrofolate Dehydrogenase
PubMed: 35050719
DOI: 10.4155/fmc-2021-0275 -
Journal of Medicinal Chemistry May 2022New antibiotics with either a novel mode of action or novel mode of inhibition are urgently needed to overcome the threat of drug-resistant tuberculosis (TB). The...
New antibiotics with either a novel mode of action or novel mode of inhibition are urgently needed to overcome the threat of drug-resistant tuberculosis (TB). The present study profiles new spiropyrimidinetriones (SPTs), DNA gyrase inhibitors having activity against drug-resistant (), the causative agent of TB. While the clinical candidate zoliflodacin has progressed to phase 3 trials for the treatment of gonorrhea, compounds herein demonstrated higher inhibitory potency against DNA gyrase (e.g., compound with IC = 2.0) and lower minimum inhibitor concentrations (0.49 μM for ). Notably, and analogues showed selective activity relative to representative Gram-positive and Gram-negative bacteria. DNA gyrase inhibition was shown to involve stabilization of double-cleaved DNA, while on-target activity was supported by hypersensitivity against a gyrA hypomorph. Finally, a docking model for SPTs with DNA gyrase was developed, and a structural hypothesis was built for structure-activity relationship expansion.
Topics: Anti-Bacterial Agents; Antitubercular Agents; DNA Gyrase; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Topoisomerase II Inhibitors
PubMed: 35500229
DOI: 10.1021/acs.jmedchem.2c00266 -
Molecular Microbiology Jun 2023DNA gyrase, the sole negative supercoiling type II topoisomerase, is composed of two subunits, GyrA and GyrB, encoded by the gyrA and gyrB genes, respectively, that form...
DNA gyrase, the sole negative supercoiling type II topoisomerase, is composed of two subunits, GyrA and GyrB, encoded by the gyrA and gyrB genes, respectively, that form a quaternary complex of A B . In this study, we have investigated the assembly of mycobacterial DNA gyrase from its individual subunits, a step prerequisite for its activity. Using analytical size-exclusion chromatography, we show that GyrA from Mycobacterium tuberculosis and Mycobacterium smegmatis forms tetramers (A ) in solution unlike in Escherichia coli and other bacteria where GyrA exists as a dimer. GyrB, however, persists as a monomer, resembling the pattern found in E. coli. GyrB in both mycobacterial species interacts with GyrA and triggers the dissociation of the GyrA tetramer to facilitate the formation of catalytically active A B . Despite oligomerisation, the GyrA tetramer retained its DNA binding ability, and DNA binding had no effect on GyrA's oligomeric state in both species. Moreover, the presence of DNA facilitated the assembly of holoenzyme in the case of M. smegmatis by stabilising the GyrA B tetramer but with little effect in M. tuberculosis. Thus, in addition to the distinct organisation and regulation of the gyr locus in mycobacteria, the enzyme assembly also follows a different pattern.
Topics: DNA Gyrase; Escherichia coli; Mycobacterium tuberculosis; Mycobacterium smegmatis; DNA, Superhelical
PubMed: 37190861
DOI: 10.1111/mmi.15068 -
EMBO Reports Jul 2023The bacterial toxin CcdB (Controller of Cell death or division B) targets DNA Gyrase, an essential bacterial topoisomerase, which is also the molecular target for...
The bacterial toxin CcdB (Controller of Cell death or division B) targets DNA Gyrase, an essential bacterial topoisomerase, which is also the molecular target for fluoroquinolones. Here, we present a short cell-penetrating 24-mer peptide, CP1-WT, derived from the Gyrase-binding region of CcdB and examine its effect on growth of Escherichia coli, Salmonella Typhimurium, Staphylococcus aureus and a carbapenem- and tigecycline-resistant strain of Acinetobacter baumannii in both axenic cultures and mouse models of infection. The CP1-WT peptide shows significant improvement over ciprofloxacin in terms of its in vivo therapeutic efficacy in treating established infections of S. Typhimurium, S. aureus and A. baumannii. The molecular mechanism likely involves inhibition of Gyrase or Topoisomerase IV, depending on the strain used. The study validates the CcdB binding site on bacterial DNA Gyrase as a viable and alternative target to the fluoroquinolone binding site.
Topics: Animals; Mice; Staphylococcus aureus; Anti-Bacterial Agents; DNA Gyrase; DNA Topoisomerase IV; Peptides
PubMed: 37166011
DOI: 10.15252/embr.202255338 -
Journal of Molecular Biology Aug 2019Type II topoisomerases regulate DNA topology by making a double-stranded break in one DNA duplex, transporting another DNA segment through this break and then resealing... (Review)
Review
Type II topoisomerases regulate DNA topology by making a double-stranded break in one DNA duplex, transporting another DNA segment through this break and then resealing it. Bacterial type IIA topoisomerase inhibitors, such as fluoroquinolones and novel bacterial topoisomerase inhibitors, can trap DNA cleavage complexes with double- or single-stranded cleaved DNA. To study the mode of action of such compounds, 21 crystal structures of a "gyrase" fusion truncate of Staphyloccocus aureus DNA gyrase complexed with DNA and diverse inhibitors have been published, as well as 4 structures lacking inhibitors. These structures have the DNA in various cleavage states and appear to track trajectories along the catalytic paths of the DNA cleavage/religation steps. The various conformations sampled by these multiple "gyrase" structures show rigid body movements of the catalytic GyrA WHD and GyrB TOPRIM domains across the dimer interface. Conformational changes common to all compound-bound structures suggest common mechanisms for DNA cleavage-stabilizing compounds. The structures suggest that S. aureus gyrase uses a single moving-metal ion for cleavage and that the central four base pairs need to be stretched between the two catalytic sites, in order for a scissile phosphate to attract a metal ion to the A-site to catalyze cleavage, after which it is "stored" in another coordination configuration (B-site) in the vicinity. We present a simplified model for the catalytic cycle in which capture of the transported DNA segment causes conformational changes in the ATPase domain that push the DNA gate open, resulting in stretching and cleaving the gate-DNA in two steps.
Topics: Anti-Bacterial Agents; Catalytic Domain; DNA; DNA Cleavage; DNA Gyrase; DNA Topoisomerases, Type I; DNA Topoisomerases, Type II; Fluoroquinolones; Metals; Models, Molecular; Protein Conformation; Quinolones; Staphylococcus aureus; Topoisomerase II Inhibitors; Topoisomerase Inhibitors
PubMed: 31301408
DOI: 10.1016/j.jmb.2019.07.008 -
Briefings in Functional Genomics Apr 2023Antimicrobial resistance in bacteria poses major challenges in selection of the therapeutic regime for managing the infectious disease. There is currently an upsurge in... (Review)
Review
Antimicrobial resistance in bacteria poses major challenges in selection of the therapeutic regime for managing the infectious disease. There is currently an upsurge in the appearance of multiple drug resistance in bacterial pathogens and a decline in the discovery of novel antibiotics. DNA gyrase is an attractive target used for antibiotic discovery due to its vital role in bacterial DNA replication and segregation in addition to its absence in mammalian organisms. Despite the presence of successful antibiotics targeting this enzyme, there is a need to bypass the resistance against this validated drug target. Hence, drug development in DNA gyrase is a highly active research area. In addition to the conventional binding sites for the novobiocin and fluoroquinolone antibiotics, several novel sites are being exploited for drug discovery. The binding sites for novel bacterial type II topoisomerase inhibitor (NBTI), simocyclinone, YacG, Thiophene and CcdB are structurally and biochemically validated active sites, which inhibit the supercoiling activity of topoisomerases. The novel chemical moieties with varied scaffolds have been identified to target DNA gyrase. Amongst them, the NBTI constitutes the most advanced DNA gyrase inhibitor which are in phase III trial of drug development. The present review aims to classify the novel binding sites other than the conventional novobiocin and quinolone binding pocket to bypass the resistance due to mutations in the DNA gyrase enzyme. These sites can be exploited for the identification of new scaffolds for the development of novel antibacterial compounds.
Topics: Animals; DNA Gyrase; Novobiocin; Anti-Bacterial Agents; Topoisomerase II Inhibitors; Mammals
PubMed: 36064602
DOI: 10.1093/bfgp/elac029