Antimicrobials Functioning through ROS-Mediated Mechanisms: Current Insights

Abstract

Antibiotic resistance and infections caused by multidrug-resistant bacteria are global health concerns. Reducing the overuse and misuse of antibiotics is the primary step toward minimizing the antibiotic resistance crisis. Thus, it is imperative to introduce and implement novel antimicrobial strategies. Recently, several alternative antimicrobials targeting oxidative stress in bacteria have been studied and shown to be promising. Oxidative stress occurs when bacterial cells fail to detoxify the excessive reactive oxygen species (ROS) accumulated in the cells. Bacteria deploy numerous defense mechanisms against oxidative stress. The oxidative stress response is not essential for the normal growth of bacteria, but it is crucial for their survival. This toxic oxidative stress is created by the host immune response or antimicrobials generating ROS. ROS possess strong oxidation potential and cause serious damage to nucleic acids, lipids, and proteins. Since ROS-based antimicrobials target multiple sites in bacteria, these antimicrobials have attracted the attention of several researchers. In this review, we present recent ROS-based alternative antimicrobials and strategies targeting oxidative stress which might help in mitigating the problem of antibiotic resistance and dissemination.

Keywords: antibiotic resistance; antimicrobials; oxidative stress; reactive oxygen species.

Figure 1

Mechanism of action of AGXX^® in S. aureus. The mode of action of AGXX^® is based on two inter-connected redox cycles resulting in its antimicrobial effect and self-renewal. In the first cycle, the chloride (Cl⁻) from the electrolyte oxidizes elementary silver (Ag⁰) to form silver chloride (AgCl). Subsequently, oxidation of organic matter like sugars in bacteria leads to the reduction of AgCl to form Ag and Cl⁻. In the second cycle, Ru^x+1 is reduced to Ru^x and reoxidized to its initial state (x is used because the precise oxidation state of ruthenium is unknown). Reoxidation of Ru^x to Ru^x+1 results in the formation of ROS such as superoxide anion, hydrogen peroxide, and highly toxic HO•. These redox cycles facilitate the constant regeneration of AGXX^®. This figure has been Adapted with permission from ref. [36]. 11 November 2021, Elsevier and from ref. [35].

Figure 2

Overview of oxidative stress in bacteria and their response to the stress. Accumulation of ROS causes oxidative stress in bacteria. Both exogenous and endogenous sources contribute to oxidative stress. ROS damage bacterial cells by causing double stranded DNA breaks, peroxidation of lipids, and by carbonylation of proteins. Bacteria respond to oxidative stress using a battery of repair mechanisms such as production of protective enzymes, metal homeostasis, SOS response, and efflux pumps. Oxidative stress response in bacteria is regulated by transcriptional factors OxyR, PerR, OhrR, and SoxRS.