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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.

SUBMITTER: Tran AT

PROVIDER: S-EPMC5337940 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

Tran Anh T AT Watson Emma E EE Pujari Venugopal V Conroy Trent T Dowman Luke J LJ Giltrap Andrew M AM Pang Angel A Wong Weng Ruh WR Linington Roger G RG Mahapatra Sebabrata S Saunders Jessica J Charman Susan A SA West Nicholas P NP Bugg Timothy D H TD Tod Julie J Dowson Christopher G CG Roper David I DI Crick Dean C DC Britton Warwick J WJ Payne Richard J RJ

Nature communications 20170301

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 o ...[more]

PMID: 28248311

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Dataset Information

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

Publications

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

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