Natural product modulators of ClpC1 with overlapping binding sites have different impacts on the <em>Mycobacterium tuberculosis</em> proteome. — ASN Events
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  3. Natural product modulators of ClpC1 with overlapping binding sites have different impacts on the Mycobacterium tuberculosis proteome.

Natural product modulators of ClpC1 with overlapping binding sites have different impacts on the Mycobacterium tuberculosis proteome. (#216)

Isabel Barter 1 2 , Paige M.E. Hawkins 1 2 , Max Bedding 1 2 , Tim Clausen 3 , Warwick J Britton 4 5 , Mark Larance 6 , 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 7, 1030,, Vienna, Austria
  4. Tuberculosis Research Program at the Centenary Institute, The University of Sydney, Sydney, NSW, Australia
  5. Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
  6. School of Medical Sciences, the University of Sydney, Sydney

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the deadliest infectious diseases globally. Antibiotics are available for TB however require a lengthy treatment timeframe of 4-6 months. (1) This is in-part due to the bacteria’s ability to switch to a dormant, non-replicating, phenotype which is inherently resistant to many antibiotics (2). Poor adherence to the lengthy treatment schedule has contributed to the consistent incidence of multiply-drug-resistant (MDR) and extensively-drug-resistant (XDR) TB cases over the past decade. (1,3) As such, there is an urgent need for new antibiotics which shorten treatment duration and operate via novel modes of action.(3)

 

Cyclomarin A, Ilamycin E and Ecumicin are cyclic peptide natural products and are some of the most potent antimycobacterial compounds to be discovered in recent years.(4) An analogue of Ecumicin, PH990 developed in house exhibited potent bactericidal activity against Mtb, capable of sterilizing cultures after seven days, and all three compounds, PH990, Cyclomarin A and Ilamycin E retain bactericidal activity against non-replicating Mtb.(5-7) These compounds bind to the N-terminal domain of ATPase chaperone ClpC1 and modulate ClpP1P2 facilitated protein degradation.(8) This presentation will describe the proteomics-based strategies which revealed the effects of the modulators on the entire proteome of Mtb. The compounds alter substrate recognition, simultaneously promoting the excessive degradation and accumulation of hundreds of different proteins. Despite structural similarities and overlapping binding sites, these compounds have strikingly different impacts on the abundance of specific proteins, including ClpC2 and Hsp.

  1. World Health Organisation, Global Tuberculosis Report 2022.
  2. Verma, A. et al. Front. Cell. Infect. Microbiol. 2022, 12.
  3. Blair, J. M. A. et al. Nat. Rev. Microbiol. 2015, 13, 42.
  4. Lee, H.; Suh J. W., Microbiol Biotechnol 2016, 43, 205.
  5. Hawkins, P. M. E. et al. J Med Chem 2022, 24, 4893.
  6. Schmitt, E. K. et al. Angew Chem int Ed Engl, 2011, 50, 5889.
  7. Choules, M. P. et al. Antimicrob Agents Chemother 2019, 63.
  8. Weinhäupl, K. et al. JBC 2022, 298.
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