Mechanisms of antibiotic resistance in Neisseria gonorrhoeae and the development of LpxC inhibitors as novel therapeutics Public Deposited

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  • March 19, 2019
Creator
  • Swanson, Shauna
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Neisseria gonorrhoeae is a Gram-negative diplococcus that causes the sexually transmitted infection gonorrhea. Antibiotics are required to treat gonorrhea. Unfortunately, the gonococcus has developed resistance to all classes of antibiotics that have been used to treat gonorrhea. Antibiotics primarily diffuse through the outer membrane porin channels into the periplasm, but we have shown that they can also access the periplasm via the outer membrane secretin PilQ; mutation or deletion of PilQ increases resistance to penicillin by approximately threefold. In its mature form, PilQ exists as an SDS-resistant multimer. However, immature PilQ monomers are also present in the outer membrane. We initiated studies to determine if antibiotic permeation occurred through the mature secretin or via immature PilQ complexes. Our data indicate that immature, SDS-labile PilQ complexes form channels that allow antibiotics to traverse the outer membrane. To help meet the growing need for new antibiotics for the treatment of gonorrhea, we have validated the enzyme LpxC as a drug target in N. gonorrhoeae. LpxC catalyzes the first committed step in the biosynthesis of lipid A, a major component of the outer membrane of Gram-negative bacteria. LpxC inhibitors are bactericidal to the gonococcus and retain activity against multi-drug resistant strains of gonorrhea. Two inhibitors were tested in vivo using the murine model of gonorrhea, and one of these inhibitors was able to clear the infection in eight out of nine infected mice. We also evaluated the capacity of N. gonorrhoeae to develop resistance to LpxC inhibitors. Spontaneously arising mutants displayed a 4- to 16-fold decrease in susceptibility to LpxC inhibitors, and in several of these mutants, mutation or deletion of the pqiA and pqiB genes was responsible for the resistance phenotype. The functions of PqiA and PqiB are unknown, but the loss of pqiAB does not alter the MICs of other antibiotics and does not affect LpxC expression or growth rate. The results of the studies described within this dissertation further our understanding of antibiotic resistance mechanisms in N. gonorrhoeae and provide the basis for the development of LpxC inhibitors as potential new therapeutics for the treatment of gonorrhea.
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  • In Copyright
Advisor
  • Wolfgang, Matthew
  • Braunstein, Miriam
  • Hobbs, Marcia
  • Richardson, Anthony
  • Nicholas, Robert
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2014
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  • Chapel Hill, NC
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  • This item is restricted from public view for 2 years after publication.
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