Invited Speaker Australian Society for Microbiology Annual Scientific Meeting 2018

Evaluation of novel inhibitors against the macrophage infectivity potentiator in Gram-negative bacteria (#97)

Jua Iwasaki 1 , Emily Kibble 1 2 , Nicole Bzdyl 1 , Chen Ai Khoo 3 , Geoff Coombs 4 , Charlene Kahler 1 , Anja Hasenkopf 5 , Peter Myler 6 7 , David Fox 6 8 , Don Lorimer 6 8 , Hayley Newton 3 , Ulrike Holzgrabe 5 , Mitali Sarkar-Tyson 1
  1. Marshall Centre for Infectious Diseases, School of Biomedical Sciences, University of Western Australia, Perth, Nedlands, WA, Australia
  2. School of Veterinary and Life Sciences, Murdoch University, Perth, WA, Australia
  3. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
  4. School of Veterinary and Life Sciences, Murdoch University, Perth, WA, Australia
  5. Institute of Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Am Hubland, 97074, Germany
  6. Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, Washington, USA
  7. Center for Infectious Disease Research, Seattle, WA 98109, USA
  8. Beryllium Discovery Corporation, Bainbridge Island, WA 98110, USA

The Macrophage infectivity potentiator (Mip) protein is a virulence factor encoded by Gram-negative intracellular pathogens. Mip proteins have been shown to have a virulence-associated peptidyl-prolyl isomerase (PPIase) activity that is important for bacterial survival and pathogenesis. Therefore, inhibition of Mip potentially represents a novel target for antimicrobial therapies towards Gram-negative bacterial pathogens. A group of pipecolic acid-derived small molecules have been shown to inhibit recombinant Mip from Burkholderia pseudomallei (Bps). Using a protease coupled PPIase assay, we have demonstrated that these compounds also have broad-spectrum inhibitory properties against the recombinant Mips from Neisseria meningitidis and Coxiella burnetii. Importantly, these inhibitors reduce the cytotoxic effects and intracellular survival of these pathogens in mammalian cell lines. Co-crystal studies of inhibitor-BpsMip complexes have aided in developing compounds with improved affinity and potency that exhibit enhanced in vitro activity against the Gram-negative bacteria investigated in these studies.