Molecular Dynamic Simulations Of Mlac Inhibition By Antibiotic In Escherichia Coli

Antimicrobial resistance has emerged as a global public health concern. Gram-negative bacteria such as Escherichia coli (E. coli) pose a significant threat to human health due to their increasing antibiotic resistance. For instance, Shiga toxin-producing E. coli (STEC) is a strain that produces toxins that cause damage to the lining of the intestines and kidneys. Antibiotic exposures to STEC would induce the hemolytic uraemic syndrome and bloody diarrhea, a potentially fatal-condition to the patient. The outer membrane architecture in Gram-negatives, specifically the OmpC–Mla complex, maintains the outer membrane lipid asymmetry. The MlaC protein transfers phospholipids from outer membranes to inner membranes and ensures the integrity of
the membrane. Inactivation of MlaC protein increases the penetrability of OM and increases the antibiotic’s sensitivity. Therefore, screening for inhibitor compounds that can bind and inhibit the function of MlaC is a viable strategy for antibiotic development.This study aims to understand the interactions of four types of inhibitors in MlaC protein from E. coli via docking and molecular dynamic (MD) simulation. The four types of inhibitors namely albacarcin V, clorobiocin, 1-N,4-N-bis(3- phenylphenyl)piperazine-1,4-dicarboxamide (piperazine dicarboxamide) and -2-[2-[(6- oxobenzo[c]chromen-2-yl)carbamoyl]phenyl]benzoic acid (salicylanilide benzoate). The docking showed that the inhibitors fit into the lipid pocket of MlaC. MD for each
system run at 100 ns showed that the system has stable Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and reasonable Radius of Gyration (Rg) value. The RMSD, RMSF and Rg were comparable to the native phospholipid binding in the crystal structure, which suggests the potential use of these four types of inhibitors. Salicylanilide benzoate was revealed to be the most stable in complex with MlaC, with the least deviation, least fluctuation, and most compact throughout the simulation