title: Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis.
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.
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Anh T
authors.initials: AT
authors.lastname: Tran
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Watson
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523, USA.
authors.forename: Venugopal
authors.initials: V
authors.lastname: Pujari
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Trent
authors.initials: T
authors.lastname: Conroy
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Dowman
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Giltrap
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Angel
authors.initials: A
authors.lastname: Pang
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA.
authors.forename: Weng Ruh
authors.initials: WR
authors.lastname: Wong
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA.|Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6.
authors.forename: Roger G
authors.identifier: 0000-0003-1818-4971
authors.initials: RG
authors.lastname: Linington
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523, USA.
authors.forename: Sebabrata
authors.initials: S
authors.lastname: Mahapatra
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University, Melbourne, Victoria 3052, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Saunders
authors.affiliation: Centre for Drug Candidate Optimisation, Monash University, Melbourne, Victoria 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.affiliation: School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: West
authors.affiliation: Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Timothy D H
authors.initials: TD
authors.lastname: Bugg
authors.affiliation: School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Tod
authors.affiliation: School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Dowson
authors.affiliation: School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: David I
authors.identifier: 0000-0003-0009-621X
authors.initials: DI
authors.lastname: Roper
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523, USA.
authors.forename: Dean C
authors.initials: DC
authors.lastname: Crick
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Warwick J
authors.initials: WJ
authors.lastname: Britton
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Payne
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D009005:Monosaccharides / Q000096:biosynthesis*; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009842:Oligopeptides / Q000096:biosynthesis* / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D014529:Uridine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D001688:Biological Products; D009005:Monosaccharides; D009842:Oligopeptides; C438940:lipid I; C519865:sansanmycin; D014529:Uridine