Mecanismos de ação antibacteriana de inibidores de tripsina: uma revisão sistemática e um estudo por simulação computacional de dinâmica molecular com membranas de bactérias

Abstract

The knowledge of new antimicrobial compounds capable of acting against microorganisms deserves attention today. Several molecules have been studied for their antibacterial activities and, among them, are trypsin inhibitors, especially the purified trypsin inhibitor from tamarind seeds (ITTp). The present work aimed to present the antibacterial action mechanisms of trypsin inhibitors through a systematic review (SR) and an in silico study of molecular dynamics (DM) simulation. For the review, studies published in the literature were gathered in order to answer the question: what are the antibacterial action mechanisms of trypsin inhibitor peptides and proteins? Initially, a SR protocol under number: CRD42020189069 was prepared and registered in the International Prospective Registry of Systematic Reviews (PROSPERO). Thus, the Preferred Reporting Items Checklist for Systematic Review and Meta-Analysis Protocols (PRISMA-P) was used to delineate the protocol and PRISMA for the systematic review. The articles were selected according to eligibility criteria, according to the PICOS (population, intervention, control, results and types of studies). The databases used were PubMed, ScienceDirect, Scopus, Web of Science, BVS and EMBASE. Original articles resulting from studies with rats and/or mice, in vitro studies (bacterial culture) and in cells were included, which described the treatments, effects and antibacterial mechanisms of peptides or proteins of the trypsin inhibitor type. Articles were selected and data were extracted by two independent reviewers. The assessment of methodological quality was performed using the OHAT (Office of Health Assessment and Translation) tool. In RS, 2382 articles were retrieved, and at the end of the search, 17 were eligible for review. It was found that most trypsin inhibitors were able to generate bacteriostatic or bactericidal effects, depending on the concentrations used. It was seen that only four studies delve into the mechanism directly in the bacterial membrane, in three studies the authors used S. aureus, E. coli. A fourth study evaluated the antibacterial action on endogenous proteases extracted from the bacteria themselves (S. enterica and S. aureus). For the DM simulation study, model number 56 was used, in conformation number 287 of the ITTp (ITTp 56/287) and the lipid bilayer model generated by the CHARMM-GUI server, to evaluate the structural behavior and interactions by DM simulations were performed using the Gromacs package 5.1.2. A greater interaction of ITTp 56/287 with the GP membrane was observed, presenting a potential energy of interaction (EPI) of –1094.97 kcal.mol1 when compared to the interaction with the Gram-negative membrane (GN), -444,337 kcal.mol1. It was possible to identify that, in the interaction ITTp 56/287-GP, the arginine amino acid residues showed higher EPI, while in the interaction ITTp 56/287-GN, they were with the residues of glutamine. This study firstly clarifies and systematizes the antibacterial action of trypsin inhibitors, being of great relevance and generating information for possible future research on these pathways. Additionally, the DM simulation study points the ITTp as a candidate for future studies that consolidate it as an option in the most effective treatment of bacterial infections.