Oxidative stress as a determinant of antimicrobial action, resistance, and treatment

Abstract

Multidrug resistance of bacterial strains due to inappropriate use of antibiotics is a great concern of current healthcare management. In the last century, the antibiotic research was mainly focused toward synthesis of new drugs for the traditional targets such as cell wall, protein, and DNA synthesis as well as understanding the bacterial counter strategies, namely, target modification, inactivation of drug, alteration of membrane permeability, active efflux of drug, etc. The shift of the paradigm of antibiotics research toward bacterial response to antibiotic action has recognized a common pathway of bactericidal antibiotic-induced oxidative stress-mediated cell killing. All bactericidal antibiotics, but not the bacteriostatic one, hyperactivate the citric acid cycle and electron transport chain and open the flood gate of reactive oxygen species (ROS) generation including the formation of highly toxic hydroxyl radical through Fenton reaction. ROS causes severe cellular damage to the biomolecules by lipid peroxidation, carbonylation of protein, and DNA strand breakage eventually leading to cell death. Bacterial stress response mechanisms counter the oxidative stress through active drug efflux, metabolic pathway modifications, synthesis of anti-oxidants, and SOS repair network, which additionally help microorganisms to acquire and propagate resistance. New treatment strategies are devised on pathogen-to-pathogen basis to overturn the resistance and potentiate the bactericidal action of antibiotics by targeting the SOS response regulatory proteins as well as increasing the ROS level at the site of infection by delivery of localized species-specific metabolites and antimicrobial agents.