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Binding of piperine to mycobacterial RNA polymerase improves the efficacy of rifampicin activity against Mycobacterium leprae and nontuberculous mycobacteria

Piperine (PPN) is a known inhibitor of efflux pumps in Mycobacterium tuberculosis and in vitro synergism with rifampicin (RIF) has been proven. The current study evaluates the activity of PPN and synergism with RIF in rapidly and slowly growing nontuberculous mycobacteria (NTM). Also, to propose a p...

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Published in:Journal of biomolecular structure & dynamics 2023-12, Vol.41 (18), p.8671-8681
Main Authors: Murase, Letícia Sayuri, Lima, Diego de Souza, Souza, João Vítor Perez de, Palomo, Carolina Trevisolli, Caleffi-Ferracioli, Katiany Rizzieri, Scodro, Regiane Bertin de Lima, Siqueira, Vera Lúcia Dias, Seixas, Flavio Augusto Vicente, Cardoso, Rosilene Fressatti
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container_issue 18
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container_title Journal of biomolecular structure & dynamics
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creator Murase, Letícia Sayuri
Lima, Diego de Souza
Souza, João Vítor Perez de
Palomo, Carolina Trevisolli
Caleffi-Ferracioli, Katiany Rizzieri
Scodro, Regiane Bertin de Lima
Siqueira, Vera Lúcia Dias
Seixas, Flavio Augusto Vicente
Cardoso, Rosilene Fressatti
description Piperine (PPN) is a known inhibitor of efflux pumps in Mycobacterium tuberculosis and in vitro synergism with rifampicin (RIF) has been proven. The current study evaluates the activity of PPN and synergism with RIF in rapidly and slowly growing nontuberculous mycobacteria (NTM). Also, to propose a possible mechanism of interaction of PPN with M. leprae (Mlp) RNA polymerase (RNAp). Minimal inhibitory concentration and drug combination assay was determined by resazurin microtiter assay and resazurin drug combination assay, respectively. In silico evaluation of PPN binding was performed by molecular docking and molecular dynamics (MD). PPN showed higher antimicrobial activity against rapidly growing NTM (32-128 mg/L) rather than for slowly growing NTM (≥ 256 mg/L). Further, 77.8% of NTM tested exhibited FICI ≤ 0.5 when exposed to PPN and RIF combination, regardless of growth speed. Docking and MD simulations showed a possible PPN binding site at the interface between β and β' subunits of RNAp, in close proximity to the trigger-helix and bridge-helix elements. MD results indicated that PPN binding hindered the mobility of these elements, which are essential for RNA transcription. We hypothesize that PPN binding might affect mycobacterial RNAp activity, and, possibly, RIF activity and that this mechanism is partially responsible for synergic behaviors with RIF reported in vitro. Communicated by Ramaswamy H. Sarma
doi_str_mv 10.1080/07391102.2022.2135602
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subjects molecular docking
mycobacterium leprae
Nontuberculous mycobacteria
piperine
RNA polymerase
title Binding of piperine to mycobacterial RNA polymerase improves the efficacy of rifampicin activity against Mycobacterium leprae and nontuberculous mycobacteria
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