Targeting the functions of the gonococcal Type IV pilus

Northwestern University At Chicago, Evanston IL

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Abstract

PROJECT SUMMARY Neisseria gonorrhoeae (Gc) is the sole causative agent of the sexually transmitted infection, gonorrhea. The rapid rise in antibiotic resistance and a recent sharp increase in reported cases in the U.S. have made this organism a target for the CDC, WHO, and NIH. This proposal will focus on the N. gonorrhoeae Type IV pilus (T4p), an essential colonization and virulence factor. We will investigate three novel aspects of Gc T4p biology that result from our ongoing studies. We have identified three small molecules that inhibit N. gonorrhoeae T4p elaboration. These chemicals inhibit the M23 class Mgp protease that targets Gc peptidoglycan (PG) to destabilize T4p elaboration. One also has N. gonorrhoeae toxicity. We will determine whether related compounds have similar inhibitory activity, how the compounds interact with Mpg, and how Mpg interacts with PG. We have discovered a novel T4p biogenesis factor we named TfpC. We will determine how TfpC alters T4p elaboration through genetic, biochemical, and physiology studies. Finally, we have shown that T4p elaboration makes N. gonorrhoeae more resistant to neutrophil-killing effectors. We have discovered that HpaC, a predicted FAD-dependent monooxygenase, differentially alters N. gonorrhoeae sensitivity to oxidative and nonoxidative killing in a pilus-dependent manner. We will determine whether HpaC does express FAD- dependent monooxygenase activity and interrogate the metabolic pathways HpaC and the pilus alter to alter sensitivity to PMN antimicrobial agents. These studies will strongly impact our understanding of N. gonorrhoeae physiology, pathogenicity, and T4p pilus biology.