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The Discovery of 2-Aminobenzimidazoles That Sensitize Mycobacterium smegmatis and M.?tuberculosis to ?-Lactam Antibiotics in a Pattern Distinct from ?-Lactamase Inhibitors.

ABSTRACT: A library of 2-aminobenzimidazole derivatives was screened for the ability to suppress ?-lactam resistance in Mycobacterium smegmatis. Several non-bactericidal compounds were identified that reversed intrinsic resistance to ?-lactam antibiotics in a manner distinct from ?-lactamase inhibitors. Activity also translates to M.?tuberculosis, with a lead compound from this study potently suppressing carbenicillin resistance in multiple M.?tuberculosis strains (including multidrug-resistant strains). Preliminary mechanistic studies revealed that the lead compounds act through a mechanism distinct from that of traditional ?-lactamase inhibitors.

SUBMITTER: Nguyen TV

PROVIDER: S-EPMC6682314 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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The Discovery of 2-Aminobenzimidazoles That Sensitize Mycobacterium smegmatis and M. tuberculosis to β-Lactam Antibiotics in a Pattern Distinct from β-Lactamase Inhibitors.

Nguyen T Vu TV Blackledge Meghan S MS Lindsey Erick A EA Minrovic Bradley M BM Ackart David F DF Jeon Albert B AB Obregón-Henao Andrés A Melander Roberta J RJ Basaraba Randall J RJ Melander Christian C

Angewandte Chemie (International ed. in English) 20170301 14

A library of 2-aminobenzimidazole derivatives was screened for the ability to suppress β-lactam resistance in Mycobacterium smegmatis. Several non-bactericidal compounds were identified that reversed intrinsic resistance to β-lactam antibiotics in a manner distinct from β-lactamase inhibitors. Activity also translates to M. tuberculosis, with a lead compound from this study potently suppressing carbenicillin resistance in multiple M. tuberculosis strains (including multidrug-resistant strains). ...[more]

PMID: 28247991

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Project description:Our current understanding of how low antibiotic concentrations shape the evolution of contemporary β-lactamases is limited. Using the widespread carbapenemase OXA-48, we tested the long-standing hypothesis that selective compartments with low antibiotic concentrations cause standing genetic diversity that could act as a gateway to developing clinical resistance. Here, we subjected Escherichia coli expressing bla OXA-48, on a clinical plasmid, to experimental evolution at sub-MICs of ceftazidime. We identified and characterized seven single variants of OXA-48. Susceptibility profiles and dose-response curves showed that they increased resistance only marginally. However, in competition experiments at sub-MICs of ceftazidime, they demonstrated strong selectable fitness benefits. Increased resistance was also reflected in elevated catalytic efficiencies toward ceftazidime. These changes are likely caused by enhanced flexibility of the Ω- and β5-β6 loops and fine-tuning of preexisting active site residues. In conclusion, low-level concentrations of β-lactams can drive the evolution of β-lactamases through cryptic phenotypes which may act as stepping-stones toward clinical resistance.IMPORTANCE Very low antibiotic concentrations have been shown to drive the evolution of antimicrobial resistance. While substantial progress has been made to understand the driving role of low concentrations during resistance development for different antimicrobial classes, the importance of β-lactams, the most commonly used antibiotics, is still poorly studied. Here, we shed light on the evolutionary impact of low β-lactam concentrations on the widespread β-lactamase OXA-48. Our data indicate that the exposure to β-lactams at very low concentrations enhances β-lactamase diversity and drives the evolution of β-lactamases by significantly influencing their substrate specificity. Thus, in contrast to high concentrations, low levels of these drugs may substantially contribute to the diversification and divergent evolution of these enzymes, providing a standing genetic diversity that can be selected and mobilized when antibiotic pressure increases.

Project description:As meropenem-clavulanic acid is recommended for the treatment of drug-resistant tuberculosis, the repurposing of new carbapenem combinations may provide new treatment options, including oral alternatives. Therefore, we studied the in vitro activities of meropenem-vaborbactam, meropenem-clavulanic acid, and tebipenem-clavulanic acid. One hundred nine Mycobacterium tuberculosis complex (MTBC) clinical isolates were tested, of which 69 were pan-susceptible and the remaining pyrazinamide- or multidrug-resistant. Broth microdilution MICs were determined using the EUCAST reference method. Meropenem and tebipenem were tested individually and in combination with vaborbactam 8 mg/L and clavulanic-acid 2 and 4 mg/L, respectively. Whole-genome sequencing was performed to explore resistance mechanisms. Clavulanic acid lowered the modal tebipenem MIC approximately 16-fold (from 16 to 1 mg/L). The modal meropenem MIC was reduced twofold by vaborbactam compared with an approximately eightfold decrease by clavulanic acid. The only previously described high-confidence carbapenem resistance mutation, crfA T62A, was shared by a subgroup of lineage 4.3.4.1 isolates and did not correlate with elevated MICs. The presence of a β-lactamase inhibitor reduced the MTBC MICs of tebipenem and meropenem. The resulting MIC distribution was lowest for the orally available drugs tebipenem-clavulanic acid. Whether this in vitro activity translates to similar or greater clinical efficacy of tebipenem-clavulanic acid compared with the currently WHO-endorsed meropenem-clavulanic acid requires clinical studies. IMPORTANCE Repurposing of already approved antibiotics, such as β-lactams in combination with β-lactamase inhibitors, may provide new treatment alternatives for drug-resistant tuberculosis. Meropenem-clavulanic acid was more active in vitro compared to meropenem-vaborbactam. Notably, tebipenem-clavulanic acid showed even better activity, raising the potential of an all-oral treatment option. Clinical data are needed to investigate whether the better in vitro activity of tebipenem-clavulanic acid correlates with greater clinical efficacy compared with the currently WHO-endorsed meropenem-clavulanic acid.

Dataset Information

The Discovery of 2-Aminobenzimidazoles That Sensitize Mycobacterium smegmatis and M.?tuberculosis to ?-Lactam Antibiotics in a Pattern Distinct from ?-Lactamase Inhibitors.

Publications

The Discovery of 2-Aminobenzimidazoles That Sensitize Mycobacterium smegmatis and M. tuberculosis to β-Lactam Antibiotics in a Pattern Distinct from β-Lactamase Inhibitors.

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