Targeting Bacterial Nitric Oxide Defenses For the Development of Novel Anti-infectives

Tue, Aug 25, 2020, 2:30 pm to 4:00 pm

The efficacies of antibiotic treatments have been compromised due to the emergence of (multi)drug-resistant pathogens, and the need for new treatment options is pressing. Within hosts, pathogens are bombarded with combinations of toxic compounds by immune cells, and bacteria evolved numerous strategies to survive those antimicrobial assaults. Disruption of those defenses could sensitize bacteria to immune attacks and lead to new anti-infective modalities. To realize such therapies, deeper understanding of how bacteria cope with those toxic cocktails is desirable. In my graduate work, we focused primarily on bacterial nitric oxide (NO) defenses and investigated how phagosomal characteristics affect bacterial resistance against NO. By imposing simultaneous oxidative and nitrosative stresses on Escherichia coli, we found that bacterial defenses against H2O2 are prioritized over those against NO. In a subsequent study, we also uncovered that DksA plays a crucial role in NO detoxification through multiple dimensions. In addition, by altering nutrient availability during growth and stress, we discovered that bacteria are better equipped to detoxify NO in amino acid deficient environments, which is relevant to those in phagosomes, and have begun to elucidate the underlying mechanism that data suggest involves the stringent response. Lastly, to find novel inhibitors of bacterial NO defenses, we performed a compound synergy screen on more than 8,000 compounds and identified 2-mercaptobenzothiazole and its analog, 2-mercaptothiazole, as strong inhibitors of NO detoxification in E. coli. As antibiotic resistance continues to pose a threat to global health, results from my thesis contribute useful knowledge for the development of antivirulence therapeutics, such as those that potentiate immunity, as novel anti-infectives.