Anti-virulence therapies through potentiating ROS in bacteria

Anti-virulence therapies represent attractive alternatives to traditional antibiotics that could bolster the therapeutic options available for bacterial infections. Such therapies impair the abilities of pathogens to infect hosts, rather than inhibit essential cellular functions, as antibiotics do. This has led to projections that resistance to anti-virulence therapies will develop on longer timescales than antibiotics. One anti-virulence strategy involves sensitizing bacteria to immune-generated reactive oxygen species (ROS), which has been motivated by the numerous pathogens that have attenuated or eliminated virulence when their ROS detoxification systems have been compromised. Several therapeutically relevant compounds that employ this strategy have been identified and initial tests have produced promising results. Here we review those compounds and the problems of realizing additional agents of this class. Notably, numerous targets within bacterial ROS defense networks are homologous to or use similar catalytic sites as those for essential human enzymes, which complicates efforts to identify efficacious antagonists. A deeper understanding of how bacteria cope with ROS will assist in the discovery and development of this class of anti-infectives and we explain how computational modeling can enrich the search for ROS-potentiating anti-virulence therapies.