Antibiotic resistant bacteria account for a large portion of infection-related morbidity and mortality, worldwide. Bacteria causing meningitis, pneumonia, and gonorrhea have been categorized as major health concerns due to the alarming rate at which they are developing resistance to traditional antibiotics. These bacteria rely on virulence factors called Immunoglobulin A1 proteases (IgA1Ps) to help them invade and colonize the host. IgA1Ps readily cleave human immunoglobulin A1 (IgA1), the predominant antibody on most of the human mucosal surfaces, impeding IgA1 from neutralizing these antigens. Targeting virulence factors is considered a safe alternative approach for the development of antibacterial drugs. Since virulence inhibitors do not target survival-related traits in bacteria, there is a reduced risk for selection pressure against inhibition. Therefore, our recent efforts have focused on the discovery of small molecule inhibitors against H. influenzae IgA1P, to help us better understand its role in pathogenicity and validating these inhibitors as potential anti-virulence drugs. We have previously developed a synthetic substrate against these IgA1Ps, which has facilitated testing of inhibitors in a High-Throughput Screening (HTS) campaign. To date, we have screened 47,839 compounds, performed follow-up assays and initial SAR on a promising series of inhibitors. This HTS campaign has produced several, selective small molecule inhibitors of H. influenzae IgA1P, which can be further improved and potentially used as therapeutics against infections.

Targeting virulence factors: Discovery of small-molecule inhibitors of Haemophilus influenzae IgA1 protease

256th National Meeting (2018)

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