Dataset Information

In vitro and in vivo activity of biapenem against drug-susceptible and rifampicin-resistant Mycobacterium tuberculosis.

ABSTRACT:

Background

Biapenem, a carbapenem antibiotic, has been shown to have synergistic bactericidal anti-TB activity when combined with rifampicin both in vitro and in the mouse model of TB chemotherapy. We hypothesized that this synergy would result in biapenem/rifampicin activity against rifampicin-resistant Mycobacterium tuberculosis .

Objectives

Our objective was to evaluate the synergy of biapenem/rifampicin against both low- and high-level rifampicin-resistant strains of M. tuberculosis , in vitro and in the mouse model.

Methods

Biapenem/rifampicin activity was evaluated using three strains of M. tuberculosis : strain 115R (low-level rifampicin resistance); strain 124R (high-level rifampicin resistance); and the drug-susceptible H37Rv parent strain. Biapenem/rifampicin synergy was evaluated in vitro by chequerboard titration. In vivo , we first conducted a dose-ranging experiment with biapenem against H37Rv in the mouse model. We then evaluated biapenem/rifampicin activity in mice infected with each M. tuberculosis strain.

Results

In vitro , synergy was observed between biapenem and rifampicin against H37Rv and strain 115R. In vivo , biapenem exhibited clear dose-dependent activity against H37Rv, with all biapenem doses as active or more active than rifampicin alone. Biapenem and rifampicin had synergistic bactericidal activity against H37Rv in the mouse model; no synergy was observed in mice infected with either of the rifampicin-resistant strains. Biapenem alone was active against all three strains.

Conclusions

Our preclinical experiments indicate that biapenem has potential for use as an anti-TB drug, including for use against rifampicin-resistant TB. Thus, biapenem has promise for repurposing as a 'new' - and desperately needed - drug for the treatment of drug-resistant TB.

SUBMITTER: Kaushik A

PROVIDER: S-EPMC5890701 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Publications

In vitro and in vivo activity of biapenem against drug-susceptible and rifampicin-resistant Mycobacterium tuberculosis.

Kaushik Amit A Ammerman Nicole C NC Tasneen Rokeya R Story-Roller Elizabeth E Dooley Kelly E KE Dorman Susan E SE Nuermberger Eric L EL Lamichhane Gyanu G

The Journal of antimicrobial chemotherapy 20170801 8

<h4>Background</h4>Biapenem, a carbapenem antibiotic, has been shown to have synergistic bactericidal anti-TB activity when combined with rifampicin both in vitro and in the mouse model of TB chemotherapy. We hypothesized that this synergy would result in biapenem/rifampicin activity against rifampicin-resistant Mycobacterium tuberculosis .<h4>Objectives</h4>Our objective was to evaluate the synergy of biapenem/rifampicin against both low- and high-level rifampicin-resistant strains of M. tuberc ...[more]

PMID: 28575382

Similar Datasets

Project description:Tuberculosis (TB), caused by the Mycobacterium tuberculosis infection, continues to be a leading cause of morbidity and mortality in developing countries. Resistance to the first-line anti-TB drugs, isoniazid (INH) and rifampicin (RIF), is a major drawback to effective TB treatment. Genetic mutations in the β-subunit of the DNA-directed RNA polymerase (rpoB) are reported to be a major reason of RIF resistance. However, the structural basis and mechanisms of these resistant mutations are insufficiently understood. In the present study, thirty drug-resistant mutants of rpoB were initially modeled and screened against RIF via a comparative molecular docking analysis with the wild-type (WT) model. These analyses prioritized six mutants (Asp441Val, Ser456Trp, Ser456Gln, Arg454Gln, His451Gly, and His451Pro) that showed adverse binding affinities, molecular interactions, and RIF binding hinderance properties, with respect to the WT. These mutant models were subsequently analyzed by molecular dynamics (MD) simulations. One-hundred nanosecond all-atom MD simulations, binding free energy calculations, and a dynamic residue network analysis (DRN) were employed to exhaustively assess the impact of mutations on RIF binding dynamics. Considering the global structural motions and protein-ligand binding affinities, the Asp441Val, Ser456Gln, and His454Pro mutations generally yielded detrimental effects on RIF binding. Locally, we found that the electrostatic contributions to binding, particularly by Arg454 and Glu487, might be adjusted to counteract resistance. The DRN analysis revealed that all mutations mostly distorted the communication values of the critical hubs and may, therefore, confer conformational changes in rpoB to perturb RIF binding. In principle, the approach combined fundamental molecular modeling tools for robust "global" and "local" level analyses of structural dynamics, making it well suited for investigating other similar drug resistance cases.

Dataset Information

In vitro and in vivo activity of biapenem against drug-susceptible and rifampicin-resistant Mycobacterium tuberculosis.

Background

Objectives

Methods

Results

Conclusions

Publications

In vitro and in vivo activity of biapenem against drug-susceptible and rifampicin-resistant Mycobacterium tuberculosis.

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