Poster Presentation 14th Australian Peptide Conference 2022

Potent bactericidal antimycobacterials targeting the chaperone ClpC1 based on the depsipeptide natural products ecumicin and ohmyungsamycin A (#107)

Isabel K Barter 1 2 , Paige M.E Hawkins 1 2 , David M Hoi 3 , Chen-Yi Cheung 4 , Trixie Wang 5 , Diana Quan 5 , Vishnu M Sasi 6 , Dennis Y Liu 7 , Roger G Linington 7 , Colin J Jackson 6 , Stefan H Oehlers 5 , Gregory M Cook 4 , Warrick J Britton 5 8 , Tim Clausen 3 , Richard J Payne 1 2
  1. School of Chemistry , The University of Sydney, Sydney, NSW, Australia
  2. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney, NSW, Australia
  3. Research Institute of Molecular Pathology (IMP), Dr-Bohr-Gasse , Vienna, Austria
  4. Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
  5. Tuberculosis Research Program at the Centenary Institute, The University of Sydney, Sydney, NSW, Australia
  6. Research School of Chemistry, Australian National University, Canberra, ACT, Australia
  7. Department of Chemistry, Simon Fraser University, Burnaby, Canada
  8. Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia

Tuberculosis (TB), caused by infection with the bacterium Mycobacterium tuberculosis (Mtb), is the most deadly infectious disease globally.1 While effective treatment options are available for TB, there has been a steady increase in the number of cases of multiply-drug-resistant (MDR) and extensively-drug-resistant (XDR) TB over the past decade, where treatment relies on the use of second-line antibiotics with increased toxicity.1-2 As such, there is an urgent need for new antibiotics which operate via novel modes of action.3

 

Ohmyungsamycin A and ecumicin are structurally related cyclic depsipeptide natural products that possess activity against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB).4-6 This presentation will describe the design and synthesis of a library of analogues of these two natural products using an efficient solid-phase synthesis and late stage macrolactamization strategy. Lead analogues possessing potent activity against Mtb in vitro (MIC 125-500 nM) will be described that also inhibit protein degradation by the mycobacterial ClpC1:ClpP1P2 protease with an associated enhancement of ClpC1 ATPase activity. The most promising analogue from the series exhibited rapid bactericidal killing activity against Mtb, capable of sterilizing cultures after seven days, and retained bactericidal activity against hypoxic non-replicating Mtb. This natural product analogue was also active in an in vivo zebrafish model of infection and displayed synergistic activity with the frontline TB drug rifampicin.

  1. World Health Organisation, Global Tuberculosis Report 2021.
  2. Blair, J. M. A. et al. Nat. Rev. Microbiol. 2015, 13, 42.
  3. Brown, E. D.; Wright, G. D., Nature 2016, 529 (7586), 336.
  4. Gao, W. et al. Org. Lett. 2014, 16, 6044.
  5. Hawkins, P. M. E. et al. Org. Lett. 2018, 20, 1019.
  6. Hawkins, P. M. E. et al. Chem. Eur. J. 2020. 26, 15200.