Oxidative Stress-Generating Antimicrobials, a Novel Strategy to Overcome Antibacterial Resistance

Abstract

Antimicrobial resistance is becoming one of the most important human health issues. Accordingly, the research focused on finding new antibiotherapeutic strategies is again becoming a priority for governments and major funding bodies. The development of treatments based on the generation of oxidative stress with the aim to disrupt the redox defenses of bacterial pathogens is an important strategy that has gained interest in recent years. This approach is allowing the identification of antimicrobials with repurposing potential that could be part of combinatorial chemotherapies designed to treat infections caused by recalcitrant bacterial pathogens. In addition, there have been important advances in the identification of novel plant and bacterial secondary metabolites that may generate oxidative stress as part of their antibacterial mechanism of action. Here, we revised the current status of this emerging field, focusing in particular on novel oxidative stress-generating compounds with the potential to treat infections caused by intracellular bacterial pathogens.

Novel Treatments against Mycobacterium tuberculosis Based on Drug Repurposing

“…Other strategies can be based on the analysis of oxidative stress-generating compounds and their combination to increase the biosynthesis of radical oxygen species (ROS) during host cell infection [ 44 , 45 ]. During phagocytosis, M. tuberculosis is exposed to oxidative stress, but this is not sufficient to kill the pathogen [ 46 ].…”

“…Several antituberculosis drugs have been tested as promising ROS-generating antimicrobials against M. tuberculosis , and the majority of them have produced an oxidative shift during infection, especially clofazimine [ 46 ], but also rifampicin and isoniazid [ 47 ]. The combination of several ROS-generating compounds could be a new solution against intracellular M. tuberculosis as it was demonstrated for other intracellular pathogens [ 44 , 45 , 48 ].…”

Alternative Anti-Infective Treatments to Traditional Antibiotherapy against Staphylococcal Veterinary Pathogens

“…In particular, resveratrol is an efflux pump inhibitor that increases the efficacy of other antimicrobials [ 27 ]. However, resveratrol is an antioxidant compound [ 58 ], and therefore, its use in combination with oxidative stress-generating antimicrobials could decrease the efficacy of the anti-staphylococcal therapy [ 59 ].…”

“…In particular, zinc oxide nanoparticles are considered a safe and low-cost therapy against many human infections [ 40 , 98 ] ( Table 2 ). Interestingly, nanoparticles have shown antimicrobial activity against intracellular pathogens because they may stimulate the biosynthesis of Reactive Oxygen Species (ROS) within subcellular compartments of the infected host cell, causing oxidative stress and damage to bacterial membranes [ 41 , 58 ]. Zinc oxide nanoparticles have broad-spectrum antimicrobial activity, and they may be useful in treating MRSA infections [ 40 , 41 ].…”

ROS Defense Systems and Terminal Oxidases in Bacteria

“…H 2 O 2 permeates freely across bacterial membranes and can react with Fe 2+ , producing a very powerful oxidant through this Fenton reaction, • OH. One more extremely dangerous ROS, 1 O 2 , can be generated by endogenous photosensitizers, such as flavins, quinones, porphyrins, and rhodopsins [4]. All these ROS, particularly • OH and 1 O 2 , can damage bacterial DNA, RNA, proteins, and lipids.…”