vCOMBAT: a novel tool to create and visualize a computational model of bacterial antibiotic target-binding

Abstract

Background As antibiotic resistance creates a significant global health threat, we need not only to accelerate the development of novel antibiotics but also to develop better treatment strategies using existing drugs to improve their efficacy and prevent the selection of further resistance. We require new tools to rationally design dosing regimens from data collected in early phases of antibiotic and dosing development. Mathematical models such as mechanistic pharmacodynamic drug-target binding explain mechanistic details of how the given drug concentration affects its targeted bacteria. However, there are no available tools in the literature that allow non-quantitative scientists to develop computational models to simulate antibiotic-target binding and its effects on bacteria. Results In this work, we have devised an extension of a mechanistic binding-kinetic model to incorporate clinical drug concentration data. Based on the extended model, we develop a novel and interactive web-based tool that allows non-quantitative scientists to create and visualize their own computational models of bacterial antibiotic target-binding based on their considered drugs and bacteria. We also demonstrate how Rifampicin affects bacterial populations of Tuberculosis bacteria using our vCOMBAT tool. Conclusions The vCOMBAT online tool is publicly available at https://combat-bacteria.org/.

The Extent of Antimicrobial Resistance Due to Efflux Pump Regulation

“…Given the ubiquitous presence of efflux pumps, it is important to quantify the extent of resistance that efflux up-regulation will confer via their induction in the wild-type strain and via chromosomal mutations that disrupt their regulation. Previous studies have employed a combination of experiments and in silico modeling to describe the uptake and efflux of drugs. − However, these models have not accounted for the regulation of efflux pump that leads to the phenotypic induction of resistance. Other studies in bacterial ,− and yeast systems , have formulated efflux pump regulation but not in the context of capturing the ensuing resistance to drugs.…”

“…Previous studies have employed a combination of experiments and in silico modeling to describe the uptake and efflux of drugs. − However, these models have not accounted for the regulation of efflux pump that leads to the phenotypic induction of resistance. Other studies in bacterial ,− and yeast systems , have formulated efflux pump regulation but not in the context of capturing the ensuing resistance to drugs. In our mathematical approach we aim to quantify the change in resistance against a drug due to the up-regulation of the efflux pump via both the phenotypic induction by the drug and genotypic abrogation of the regulator leading to disrupted efflux regulation.…”