Potent Bactericidal Antimycobacterials Targeting the Chaperone ClpC1 Based on the Depsipeptide Natural Products Ecumicin and Ohmyungsamycin A

Paige M E Hawkins; David M Hoi; Chen-Yi Cheung; Trixie Wang; Diana Quan; Vishnu Mini Sasi; Dennis Y Liu; Roger G Linington; Colin J Jackson; Stefan H Oehlers; Gregory M Cook; Warwick J Britton; Tim Clausen; Richard J Payne

doi:10.1021/acs.jmedchem.1c02122

Potent Bactericidal Antimycobacterials Targeting the Chaperone ClpC1 Based on the Depsipeptide Natural Products Ecumicin and Ohmyungsamycin A

J Med Chem. 2022 Mar 24;65(6):4893-4908. doi: 10.1021/acs.jmedchem.1c02122. Epub 2022 Mar 16.

Authors

Paige M E Hawkins^{1

2}, David M Hoi³, Chen-Yi Cheung⁴, Trixie Wang⁵, Diana Quan⁵, Vishnu Mini Sasi⁶, Dennis Y Liu⁷, Roger G Linington⁷, Colin J Jackson⁶, Stefan H Oehlers⁵, Gregory M Cook⁴, Warwick J Britton^{5

8}, Tim Clausen³, Richard J Payne^{1

2}

Affiliations

¹ School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.
² Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney, New South Wales 2006, Australia.
³ Research Institute of Molecular Pathology (IMP), Dr-Bohr-Gasse 7, Vienna 1030, Austria.
⁴ Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, P.O. Box 56, Dunedin 9016, New Zealand.
⁵ Tuberculosis Research Program at the Centenary Institute, The University of Sydney, Sydney, New South Wales 2006, Australia.
⁶ Research School of Chemistry, Australian National University, Acton, 2601 Australian Capital Territory, Australia.
⁷ Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
⁸ Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales 2006, Australia.

PMID: 35293761
DOI: 10.1021/acs.jmedchem.1c02122

Abstract

Ohmyungsamycin A and ecumicin are structurally related cyclic depsipeptide natural products that possess activity against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Herein, we 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 possessed potent activity against Mtb in vitro (minimum inhibitory concentration 125-500 nM) and were shown to 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 7 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antitubercular Agents / pharmacology
Bacterial Proteins / metabolism
Biological Products* / pharmacology
Depsipeptides* / pharmacology
Molecular Chaperones
Mycobacterium tuberculosis* / metabolism
Peptides, Cyclic
Zebrafish / metabolism

Substances

Antitubercular Agents
Bacterial Proteins
Biological Products
Depsipeptides
Molecular Chaperones
Peptides, Cyclic
ecumicin
ohmyungsamycin A