Mycolic Acids: From Chemistry to Biology

Daffé, Mamadou; Quémard, Annaık̈; Marrakchi, Hédia

doi:10.1007/978-3-319-43676-0_18-1

Cited by 17 publications

(10 citation statements)

References 176 publications

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“…It plays a critical role during infection by protecting intracellular (pathogenic) mycobacteria from the harsh environment of the phagosomal compartment (Gengenbacher and Kaufmann, 2012) and it acts as a permeability barrier for antibiotics in non-replicating nutrient-starved Mtb (Sarathy et al, 2013). Various topographies have been proposed for the cell envelope of mycobacteria with the most widely accepted model introducing a schematic division into three subdomains, the outer capsule, the tripartite cell wall consisting of the outer membrane (OM) bound to arabinogalactan-peptidoglycan complex, and the inner membrane (IM) (Daffé and Marrakchi, 2017). Roughly 10% of the Mtb genome is functionally devoted to the cell wall including a large number of genes essential for growth (Sassetti et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Novel Acetamide Indirectly Targets Mycobacterial Transporter MmpL3 by Proton Motive Force Disruption

Shetty

Lakshmanan

et al. 2018

Front. Microbiol.

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To identify novel inhibitors of Mycobacterium tuberculosis cell envelope biosynthesis, we employed a two-step approach. First, we screened the diverse synthetic small molecule 71,544-compound Enamine library for growth inhibitors using the non-pathogenic surrogate Mycobacterium bovis BCG as screening strain and turbidity as readout. Second, 16 confirmed hits were tested for their ability to induce the cell envelope stress responsive promoter piniBAC controlling expression of red fluorescent protein in an M. bovis BCG reporter strain. Using a fluorescence readout, the acetamide E11 was identified. Resistant mutant selection and whole genome sequencing revealed the mycolic acid transporter Mmpl3 as a candidate target of E11. Biochemical analysis using mycobacterial spheroplasts and various membrane assays suggest that E11 indirectly inhibits MmpL3-facilitated translocation of trehalose monomycolates by proton motive force disruption. E11 showed potent bactericidal activity against growing and non-growing M. tuberculosis, low cytotoxic, and hemolytic activity and a dynamic structure activity relationship. In addition to activity against M. tuberculosis, E11 was active against the non-tuberculous mycobacterium M. abscessus, an emerging opportunistic pathogen. In conclusion, we identified a novel bactericidal anti-mycobacterial lead compound targeting MmpL3 providing an attractive starting point for optimization.

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Section: Introductionmentioning

confidence: 99%

Novel Acetamide Indirectly Targets Mycobacterial Transporter MmpL3 by Proton Motive Force Disruption

Shetty

Lakshmanan

et al. 2018

Front. Microbiol.

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“…This was likely due to the thick (40–100 nm) and highly complex mycobacterial cell wall . The mycobacterial cell wall contains multiple layers of (peptido)glycans and lipids, including the ultralipophilic mycolic acids that can be up to 90 carbons in length . In practice, this results in hydrophobic aggregation of bacteria (especially after fixation) and an impermeability to the ccHc-reactive fluorophores.…”

Section: Resultsmentioning

confidence: 99%

“…51 The mycobacterial cell wall contains multiple layers of (peptido)glycans and lipids, including the ultralipophilic mycolic acids that can be up to 90 carbons in length. 52 In practice, this results in hydrophobic aggregation of bacteria (especially after fixation) and an impermeability to the ccHc-reactive fluorophores. We postulated this would reduce the yields of the two ccHc-reactions.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Bioorthogonal Correlative Light-Electron Microscopy of Mycobacterium tuberculosis in Macrophages Reveals the Effect of Antituberculosis Drugs on Subcellular Bacterial Distribution

et al. 2020

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Bioorthogonal correlative light-electron microscopy (B-CLEM) can give a detailed overview of multicomponent biological systems. It can provide information on the ultrastructural context of bioorthogonal handles and other fluorescent signals, as well as information about subcellular organization. We have here applied B-CLEM to the study of the intracellular pathogen Mycobacterium tuberculosis ( Mtb ) by generating a triply labeled Mtb through combined metabolic labeling of the cell wall and the proteome of a DsRed-expressing Mtb strain. Study of this pathogen in a B-CLEM setting was used to provide information about the intracellular distribution of the pathogen, as well as its in situ response to various clinical antibiotics, supported by flow cytometric analysis of the bacteria, after recovery from the host cell ( ex cellula ). The RNA polymerase-targeting drug rifampicin displayed the most prominent effect on subcellular distribution, suggesting the most direct effect on pathogenicity and/or viability, while the cell wall synthesis-targeting drugs isoniazid and ethambutol effectively rescued bacterial division-induced loss of metabolic labels. The three drugs combined did not give a more pronounced effect but rather an intermediate response, whereas gentamicin displayed a surprisingly strong additive effect on subcellular distribution.

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“…β-ketoacyl-ACP synthases (KasA and KasB) catalyzes new acyl extension cycles with a new malonyl-ACP unit, thereby extending the growing meromycolate chain by two carbon units to form a β-ketoacyl-ACP from acyl-ACP and malonyl-ACP [17,18]. Finally, last Claisen-type condensation step catalyzed by polyketide synthase (Pks13) that connects the mero-mycolic chain to a carboxylated α-chain produced by FAS-I that synthesizes trehalose mycolic β-ketoester and reduced by CmrA to trehalose monomycolate (TMM), a form of mature mycolic acid in Mtb [19,20,21]. The detailed biosynthesis pathway of mycolic acid is displayed in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

In silico identification of novel chemical compounds with anti-TB potential for the inhibition of InhA and EthR from Mycobacterium tuberculosis

Halder

Elma

2020

Preprint

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Tuberculosis (TB) continuously pose a major public health concern around the globe, with a mounting death toll of approximately 1.4 million in 2019. The reduced bioavailability, increased toxicity and resistance of several first-line and second-line anti-TB drugs such as isoniazid, ethionamide have necessitated the search for new medications. In this research, we have identified several novel chemical compounds with anti-TB properties using various computational tools like molecular docking analysis, drug-likeness evaluation, ADMET profiling, P450 site of metabolism prediction and molecular dynamics simulation study. This study involves fifty drug-like compounds with antibacterial activity that inhibit InhA and EthR involved in the synthesis of one of the major lipid components, mycolic acid, which is crucial for the viability of Mycobacterium tuberculosis. Among these fifty compounds, 3-[3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl]-N-(2-methylphenyl) piperidine-1-carboxamide (C22) and 5-(4-Ethyl-phenyl)-2-(1H-tetrazol-5-ylmethyl)-2H-tetrazole (C29) were found to pass the two-step molecular docking, P450 site of metabolism prediction and pharmacokinetics filtering analysis successfully. Their binding stability for target proteins have been evaluated through RMSD, RMSF, Radius of gyration analysis from 10 ns Molecular Dynamics Simulation (MDS) run. Our identified drugs could be a capable therapeutic for Tuberculosis drug discovery, having said that more in vitro and in vivo testing is required to justify their potential as novel drug and mode of action.

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Mycolic Acids: From Chemistry to Biology

Cited by 17 publications

References 176 publications

Novel Acetamide Indirectly Targets Mycobacterial Transporter MmpL3 by Proton Motive Force Disruption

Novel Acetamide Indirectly Targets Mycobacterial Transporter MmpL3 by Proton Motive Force Disruption

Bioorthogonal Correlative Light-Electron Microscopy of Mycobacterium tuberculosis in Macrophages Reveals the Effect of Antituberculosis Drugs on Subcellular Bacterial Distribution

In silico identification of novel chemical compounds with anti-TB potential for the inhibition of InhA and EthR from Mycobacterium tuberculosis

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