Mycobacterium Tuberculosis (MTB) GyrB inhibitors: An attractive approach for developing novel drugs against TB

Chaudhari, Kavita; Surana, Sanjay J.; Jain, Pritam S.; Patel, Harun

doi:10.1016/j.ejmech.2016.08.034

Cited by 59 publications

(32 citation statements)

References 102 publications

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“…That reaction, the structure of gyrase, and the effects of inhibitors such as the FQs have been studied and reviewed in considerable detail (e.g., [9–11]). Gyrase is a clinically validated, structurally tractable target for antibacterial drug development, and in recent years a considerable number of non-FQ gyrase inhibitors have been described and reviewed [12, 13]. Bacterial topoisomerase II inhibitors can be divided into two broad categories; those that inhibit the essential ATPase function of the B subunit and those that inhibit gyrase in a different manner.…”

Section: Introductionmentioning

confidence: 99%

Antibacterial small molecules targeting the conserved TOPRIM domain of DNA gyrase

et al. 2017

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To combat the threat of antibiotic-resistant Gram-negative bacteria, novel agents that circumvent established resistance mechanisms are urgently needed. Our approach was to focus first on identifying bioactive small molecules followed by chemical lead prioritization and target identification. Within this annotated library of bioactives, we identified a small molecule with activity against efflux-deficient Escherichia coli and other sensitized Gram-negatives. Further studies suggested that this compound inhibited DNA replication and selection for resistance identified mutations in a subunit of E. coli DNA gyrase, a type II topoisomerase. Our initial compound demonstrated weak inhibition of DNA gyrase activity while optimized compounds demonstrated significantly improved inhibition of E. coli and Pseudomonas aeruginosa DNA gyrase and caused cleaved complex stabilization, a hallmark of certain bactericidal DNA gyrase inhibitors. Amino acid substitutions conferring resistance to this new class of DNA gyrase inhibitors reside exclusively in the TOPRIM domain of GyrB and are not associated with resistance to the fluoroquinolones, suggesting a novel binding site for a gyrase inhibitor.

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Section: Introductionmentioning

confidence: 99%

Antibacterial small molecules targeting the conserved TOPRIM domain of DNA gyrase

et al. 2017

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“…The topoisomerases enzymes are involved in maintaining the DNA topology during DNA replication, transcription, translation, and recombination in prokaryotic and eukaryotic cells. Therefore the inhibition of DNA gyrase results in cell death . DNA gyrase is a heterotetramer containing two A and B subunits each .…”

Section: Fluoroquinolonesmentioning

confidence: 99%

“…The phenolic OH group of this tyrosine moiety acts as a nucleophile that cleaves the phosphodiester bonds of DNA . The GyrB subunit contains an ATP‐binding pocket which helps in the ATP hydrolysis . The absence of this enzyme in eukaryotes, makes it an attractive target for developing novel TB drugs …”

Section: Fluoroquinolonesmentioning

confidence: 99%

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An overview of new antitubercular drugs, drug candidates, and their targets

Bahuguna

Rawat

2019

Medicinal Research Reviews

140

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The causative agent of tuberculosis (TB), Mycobacterium tuberculosis and more recently totally drug‐resistant strains of M. tuberculosis, display unique mechanisms to survive in the host. A four‐drug treatment regimen was introduced 40 years ago but the emergence of multidrug‐resistance and more recently TDR necessitates the identification of new targets and drugs for the cure of M. tuberculosis infection. The current efforts in the drug development process are insufficient to completely eradicate the TB epidemic. For almost five decades the TB drug development process remained stagnant. The last 10 years have made sudden progress giving some new and highly promising drugs including bedaquiline, delamanid, and pretomanid. Many of the candidates are repurposed compounds, which were developed to treat other infections but later, exhibited anti‐TB properties also. Each class of drug has a specific target and a definite mode of action. These targets are either involved in cell wall biosynthesis, protein synthesis, DNA/RNA synthesis, or metabolism. This review discusses recent progress in the discovery of newly developed and Food and Drug Administration approved drugs as well as repurposed drugs, their targets, mode of action, drug‐target interactions, and their structure‐activity relationship.

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“…As a proof of concept, we screened Vichem’s compound library (639 compounds) and identified 108 compounds that bind to specific sites of MtTopo-I [18, 19]. Recently, the homology model and the crystal structure of MtTopo-I has been published, opening the way for rational design of inhibitors [17, 20–24]. From among the positive hits with benzo(g)-quinoxaline, quinoxaline or styryl-benzo(g)-quinazoline scaffolds, in the present work we selected 7 compounds for further characterization.…”

Section: Introductionmentioning

confidence: 99%

Characterization of new, efficient Mycobacterium tuberculosis topoisomerase-I inhibitors and their interaction with human ABC multidrug transporters

Temesszentandrási-Ambrus

Tóth

Verma

et al. 2018

PLoS ONE

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Drug resistant tuberculosis (TB) is a major worldwide health problem. In addition to the bacterial mechanisms, human drug transporters limiting the cellular accumulation and the pharmacological disposition of drugs also influence the efficacy of treatment. Mycobacterium tuberculosis topoisomerase-I (MtTopo-I) is a promising target for antimicrobial treatment. In our previous work we have identified several hit compounds targeting the MtTopo-I by in silico docking. Here we expand the scope of the compounds around three scaffolds associated with potent MtTopo-I inhibition. In addition to measuring the effect of newly generated compounds on MtTopo-I activity, we characterized the compounds’ antimicrobial activity, toxicity in human cells, and interactions with human multidrug transporters. Some of the newly developed MtTopo-I inhibitors have strong antimicrobial activity and do not harm mammalian cells. Moreover, our studies revealed significant human ABC drug transporter interactions for several MtTopo-I compounds that may modify their ADME-Tox parameters and cellular effects. Promising new drug candidates may be selected based on these studies for further anti-TB drug development.

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Mycobacterium Tuberculosis (MTB) GyrB inhibitors: An attractive approach for developing novel drugs against TB

Cited by 59 publications

References 102 publications

Antibacterial small molecules targeting the conserved TOPRIM domain of DNA gyrase

Antibacterial small molecules targeting the conserved TOPRIM domain of DNA gyrase

An overview of new antitubercular drugs, drug candidates, and their targets

Characterization of new, efficient Mycobacterium tuberculosis topoisomerase-I inhibitors and their interaction with human ABC multidrug transporters

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