Novel therapeutics against multi-drug resistant Neisseria gonorrhoeae

Neisseria gonorrhoea is the bacteria causing the sexually transmitted infection (STI) gonorrhoea. In 2012-2013, the World Health Organization (WHO) declared the multi-drug resistant N. gonorrhoea one of three immediate threats to public health.

This is because N. gonorrhoea has developed resistance to all major categories of antibiotics, including the last line antibiotics, third-generation cephalosporins, resulting in an increase in treatment failures.

In 2011, WHO estimated 78 million new cases of sexually transmitted infections each year were attributable to N. gonorrhoea. In men, acute urethritis and repeat infections can reduce fertility but are not life threatening. In women, it can result in pelvic inflammatory disease, ectopic pregnancy and increased risk of abortion.

This project aims to develop new treatments using small molecule inhibitors against a series of virulence determinants involved in development of this bacteria. Our overall goal is to design and test small molecule inhibitors against multiple virulence targets in Neisseria gonorrhoea, and we have received two funding grants from the National Health and Research Council to do this. Our research is led by the head of UWA’s Infection and Immunity Division, Associate Professor Charlene Kahler.

For more information on our research, see the readings below:

• Multidrug-resistant Neisseria gonorrhoeae: future therapeutic options. CM Kahler (2018) Future microbiology 13 (5), 499-501; Structure of a lipid A phosphoethanolamine transferase suggests how conformational changes govern substrate binding. (2017)
• Anandhi Anandan, Genevieve L. Evans, Karmen Condic-Jurkic, Megan L. O’Mara, Constance M. John, Nancy J. Phillips, Gary A. Jarvis, Siobhan S. Wills, Keith A. Stubbs, Isabel Moraes, Charlene M. Kahler and Alice Vrielink. PNAS 114 (9) 2218-2223; Inhibitors of macrophage infectivity potentiator-like PPIases affect neisserial and chlamydial pathogenicity.
• Anastasija Reimer, Florian Seufert, Matthias Weiwad, Jutta Ebert, Nicole M Bzdyl, Charlene M Kahler, Mitali Sarkar-Tyson, Ulrike Holzgrabe, Thomas Rudel, Vera Kozjak-Pavlovic. (2016) International journal of antimicrobial agents 48 (4), 401-408; Production, biophysical characterization and initial crystallization studies of the N-and C-terminal domains of DsbD, an essential enzyme in Neisseria meningitidis.(2018)
• RP Smith, AE Whitten, JJ Paxman, CM Kahler, MJ Scanlon, B Heras. Structural Biology and Crystallization Communications 74 (1), 31-38; The structure of the bacterial oxidoreductase enzyme DsbA in complex with a peptide reveals a basis for substrate specificity in the catalytic cycle of DsbA enzymes. 2009.
• Jason J Paxman, Natalie A Borg, James Horne, Philip E Thompson, Yanni Chin, Pooja Sharma, Jamie S Simpson, Jerome Wielens, Susannah Piek, Charlene M Kahler, Harry Sakellaris, Mary Pearce, Stephen P Bottomley, Jamie Rossjohn, Martin J Scanlon. Journal of Biological chemistry, 284: 17835-17845; The Structure of the Bacterial Oxidoreductase Enzyme DsbA in Complex with a Peptide Reveals a Basis for Substrate Specificity in the Catalytic Cycle of DsbA Enzymes