The development of antibiotic resistance poses a serious threat to global health and modern medicine. Antibiotics are used not only to treat infectious diseases but also as a precaution to prevent complications after invasive medical procedures. Over time, bacteria have developed and disseminated defenses against these live-saving drugs, leading to increasing failures of antibiotic treatments, which include last resort treatments. To try to assuage this advancing health crisis, we sought to develop novel anti-infectives by targeting pathogens’ virulence, and specifically their defenses against nitrosative stress. Nitric oxide (NO) is synthesized by phagocytes, which constitute the body’s first line of defense, to eliminate invading bacteria. However, various pathogens have developed defenses against nitric oxide, allowing them to withstand immune attack, proliferate in the host and ultimately cause an illness. We aimed to identify inhibitors of bacterial NO defenses by screening for molecules that impede bacterial growth in the presence of NO, but not its absence. Of more than 8,000 compounds screened, we found 4 hits that hold promising properties. Among them, 2-mercaptobenzothiazole (2-MBT), is especially interesting because it can nearly completely thwart the aerobic NO detoxification in Escherichia coli, while not significantly undermining growth under normal growth conditions. Preliminary results suggest that 2-MBT is a direct inhibitor of the Hmp pathway, which is responsible for detoxifying NO under oxygenated conditions in E. coli. Current effort is focusing on elucidating the mechanism of action of 2-MBT, and studying the potency of its analogs to identify chemical components that are essential for its inhibitory effects.

Small molecule screening for inhibitors of Escherichia coli nitric oxide defense

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.