Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

Anh T. Tran, Emma E. Watson, Venugopal Pujari, Trent Conroy, Luke J. Dowman, Andrew M. Giltrap, Angel Pang, Weng Ruh Wong, Roger G. Linington, Sebabrata Mahapatra, Jessica Saunders, Susan A. Charman, Nicholas P. West, Timothy D. H. Bugg, Julie Tod, Christopher G. Dowson, David I. Roper, Dean C. Crick, Warwick J. Britton and Richard J. Payne ()
Additional contact information
Anh T. Tran: School of Chemistry, The University of Sydney
Emma E. Watson: School of Chemistry, The University of Sydney
Venugopal Pujari: Mycobacteria Research Laboratories, Immunology and Pathology, Colorado State University
Trent Conroy: School of Chemistry, The University of Sydney
Luke J. Dowman: School of Chemistry, The University of Sydney
Andrew M. Giltrap: School of Chemistry, The University of Sydney
Angel Pang: Centenary Institute and Sydney Medical School, The University of Sydney
Weng Ruh Wong: University of California
Roger G. Linington: University of California
Sebabrata Mahapatra: Mycobacteria Research Laboratories, Immunology and Pathology, Colorado State University
Jessica Saunders: Centre for Drug Candidate Optimisation, Monash University
Susan A. Charman: Centre for Drug Candidate Optimisation, Monash University
Nicholas P. West: School of Chemistry and Molecular Biosciences, University of Queensland
Timothy D. H. Bugg: University of Warwick
Julie Tod: School of Life Sciences, University of Warwick
Christopher G. Dowson: School of Life Sciences, University of Warwick
David I. Roper: School of Life Sciences, University of Warwick
Dean C. Crick: Mycobacteria Research Laboratories, Immunology and Pathology, Colorado State University
Warwick J. Britton: Centenary Institute and Sydney Medical School, The University of Sydney
Richard J. Payne: School of Chemistry, The University of Sydney

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: Abstract Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis.

Date: 2017
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DOI: 10.1038/ncomms14414

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