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
Postgraduate Program in Health Sciences, State University of Maringa, Maringa, Brazil.
Postgraduate Program in Biological Sciences, State University of Maringa, Maringa, Brazil.
J Biomol Struct Dyn. 2023 Oct-Nov;41(18):8671-8681. doi: 10.1080/07391102.2022.2135602. Epub 2022 Oct 18.
Piperine (PPN) is a known inhibitor of efflux pumps in and 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 (Mlp) RNA polymerase (RNAp). Minimal inhibitory concentration and drug combination assay was determined by resazurin microtiter assay and resazurin drug combination assay, respectively. 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 . Communicated by Ramaswamy H. Sarma.
胡椒碱（PPN）是一种已知的外排泵抑制剂，并且已证实其与利福平（RIF）具有协同作用。本研究评估了PPN在快速生长和缓慢生长的非结核分枝杆菌（NTM）中的活性以及与RIF的协同作用。此外，还提出了PPN与耻垢分枝杆菌（Mlp）RNA聚合酶（RNAp）相互作用的可能机制。分别通过刃天青微量滴定法和刃天青药物联合测定法确定最低抑菌浓度和药物联合测定。通过分子对接和分子动力学（MD）对PPN结合进行评估。PPN对快速生长的NTM（32 - 128mg/L）显示出比缓慢生长的NTM（≥256mg/L）更高的抗菌活性。此外，无论生长速度如何，77.8%的受试NTM在暴露于PPN和RIF联合用药时表现出FICI≤0.5。对接和MD模拟显示在RNAp的β亚基和β'亚基之间的界面处存在一个可能的PPN结合位点，紧邻触发螺旋和桥螺旋元件。MD结果表明PPN结合阻碍了这些对RNA转录至关重要的元件的移动。我们假设PPN结合可能会影响分枝杆菌RNAp活性，并且可能影响RIF活性，并且这种机制部分解释了所报道的与RIF的协同行为。由Ramaswamy H. Sarma传达。
