Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis
Year: 2017
Type: article
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.
Source: Nature Communications
DOI: 10.1038/ncomms14414
Authors: 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, Richard J. Payne
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Colorado State University, University of St Andrews, New South Wales Government, National Institutes of Health, Medical Research Council, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, National Health and Medical Research Council, National Institute of Allergy and Infectious Diseases
Awards: MICA: Mechanistic understanding of cell wall biosynthesis to combat antimicrobial resistance, Menaquinone biosynthesis: a drug target in Gram-positive bacteria, International exploitation of new reagents and assays for antibiotic discovery, G1846024742, HTS assays for the methylerythritol-4-phosphate pathway, G3427835625, Discovery of New Tuberculosis Drug Leads Targeting Cell Wall Biosynthesis, Cross-scale prediction of Antimicrobial Resistance: from molecules to populations., Tools and Reagents for Next Generation Inhibitor Discovery in Peptidoglycan biosynthesis, Menaquinone Biosynthesis: A Drug Target in Gram-Positive Bacteria, Enabling exploitation of novel reagents and assays (EnRgy) to target the inhibition of peptidoglycan biosynthesis, Development and validation of new reagents and assays to exploit the final steps of peptidoglycan construction, G9000019692
OpenAlex ID: W2594473237