Insight about cell wall remodulation triggered by rifampicin in Mycobacterium tuberculosis

Meneguello, Jean Eduardo; Arita, Gláucia Sayuri; Silva, João Vitor de Oliveira; Ghiraldi-Lopes, Luciana Dias; Caleffi-Ferracioli, Katiany Rizzieri; Siqueira, Vera Lúcia Dias; Scodro, Regiane Bertin de Lima; Pilau, Eduardo Jorge; Campanerut-Sá, Paula Aline Zannetti; Cardoso, Rosilene Fressatti

doi:10.1016/j.tube.2020.101903

Cited by 10 publications

(3 citation statements)

References 39 publications

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“…FabD, the malonyl transacylase, is the first of five enzymes (fabD, acpM, kasA, kasB, and accD6) responsible for fatty acid elongation ( 64 , 65 ). The role of the encoding gene, fabD, during the stress response is unclear, as it was underrepresented after exposure to rifampicin ( 66 ), upregulated in the presence of isoniazid ( 67 ), and overexpressed after the removal of a stressor ( 68 ). Nonetheless, it has frequently been associated with drug resistance ( 67 , 69 ), indicating its importance for survival after exposure to antibiotics.…”

Section: Resultsmentioning

confidence: 99%

In SilicoDrug Discovery Strategies Identified ADMET Properties of Decoquinate RMB041 and Its Potential Drug Targets against Mycobacterium tuberculosis

2022

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This article elaborates on the mechanism of action of a novel antibiotic compound against both, active and dormant Mycobacterium tuberculosis and describes its pharmacokinetics (including oral bioavailability and toxicity). Information provided in this article serves useful during the search for drugs that shorten the treatment regimen for Tuberculosis and cause minimal adverse effects.

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Section: Resultsmentioning

confidence: 99%

In SilicoDrug Discovery Strategies Identified ADMET Properties of Decoquinate RMB041 and Its Potential Drug Targets against Mycobacterium tuberculosis

2022

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“…FabD, the malonyl transacylase, is the first of five enzymes (fabD, acpM, kasA, kasB, and accD6) responsible for fatty acid elongation (67,68). The role of the encoding gene, fabD, during the stress response is unclear, as it was underrepresented after exposure to rifampicin (69), upregulated in the presence of isoniazid (70), and overexpressed after the removal of a stressor (71). Nonetheless, it has frequently been associated with drug resistance (70,72), indicating it's importance for survival after exposure to antibiotics.…”

Section: Identification and Prioritization Of Drug Targetsmentioning

confidence: 99%

In silicodrug discovery strategies identified ADMET properties of decoquinate RMB041 and its potential drug targets againstMycobacterium Tuberculosis

Knoll

Walt

Loots

2021

Preprint

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The highly adaptive cellular response of Mycobacterium tuberculosis to various antibiotics and the high costs for clinical trials, hampers the development of novel antimicrobial agents with improved efficacy and safety. Subsequently, in silico drug screening methods are more commonly being used for the discovery and development of drugs, and have been proven useful for predicting the pharmacokinetics, toxicities, and targets, of prospective new antimicrobial agents. In this investigation we used a reversed target fishing approach to determine potential hit targets and their possible interactions between M. tuberculosis and decoquinate RMB041, a propitious new antituberculosis compound. Two of the thirteen identified targets, Cyp130 and BlaI, were strongly proposed as optimal drug-targets for dormant M. tuberculosis, of which the first showed the highest comparative binding affinity to decoquinate RMB041. The metabolic pathways associated to the selected target proteins were compared to previously published molecular mechanisms of decoquinate RMB041 against M. tuberculosis, whereby we confirmed disrupted metabolism of proteins, cell wall components, and DNA. We also described the steps within these pathways that are inhibited and elaborated on decoquinate RMB041’s activity against dormant M. tuberculosis. This compound has previously showed promising in vitro safety and good oral bioavailability, which were both supported by this in silico study. The pharmacokinetic properties and toxicity of this compound were predicted and investigated using the online tools pkCSM and SwissADME, and Discovery Studio software, which furthermore supports previous safety and bioavailability characteristics of decoquinate RMB041 for use as an antimycobacterial medication.

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“…Proteomics has helped to deconvolute M.tb responses to drug exposure providing insight into mechanisms of drug action and resistance [86]. Recently, Meneguello et al used proteomics to explore the metabolic pathways that contribute to the activity of rifampicin [87]. A small percentage of rifampicin resistance occurs through mechanisms other than the well-characterized target, β subunit of RNA polymerase.…”

Section: Mode Of Actionmentioning

confidence: 99%

Multi-Omics Technologies Applied to Tuberculosis Drug Discovery

et al. 2020

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Multi-omics strategies are indispensable tools in the search for new anti-tuberculosis drugs. Omics methodologies, where the ensemble of a class of biological molecules are measured and evaluated together, enable drug discovery programs to answer two fundamental questions. Firstly, in a discovery biology approach, to find new targets in druggable pathways for target-based investigation, advancing from target to lead compound. Secondly, in a discovery chemistry approach, to identify the mode of action of lead compounds derived from high-throughput screens, progressing from compound to target. The advantage of multi-omics methodologies in both of these settings is that omics approaches are unsupervised and unbiased to a priori hypotheses, making omics useful tools to confirm drug action, reveal new insights into compound activity, and discover new avenues for inquiry. This review summarizes the application of Mycobacterium tuberculosis omics technologies to the early stages of tuberculosis antimicrobial drug discovery.

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Insight about cell wall remodulation triggered by rifampicin in Mycobacterium tuberculosis

Cited by 10 publications

References 39 publications

In SilicoDrug Discovery Strategies Identified ADMET Properties of Decoquinate RMB041 and Its Potential Drug Targets against Mycobacterium tuberculosis

In SilicoDrug Discovery Strategies Identified ADMET Properties of Decoquinate RMB041 and Its Potential Drug Targets against Mycobacterium tuberculosis

In silicodrug discovery strategies identified ADMET properties of decoquinate RMB041 and its potential drug targets againstMycobacterium Tuberculosis

Multi-Omics Technologies Applied to Tuberculosis Drug Discovery

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