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

Anh Tran ,Emma E Watson,Julie Tod,Weng Ruh Wong,Sebabrata Mahapatra,Angel Pang,Luke J Dowman,Roger G Linington,Jessica Saunders,Andrew M Giltrap,Warwick J Britton,Christopher G Dowson,David I Roper,Susan A Charman,Venugopal Pujari,Dean C Crick,Nicholas P West,Trent Conroy,Timothy D H Bugg,Richard J Payne

doi:10.1038/ncomms14414

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.

Highlights

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
In addition to these fascinating structural features, the natural products have been shown to possess significant activity against Mycobacterium tuberculosis (Mtb), including multi-drug resistant (MDR) strains[14,15]. For these reasons we became interested in the sansanmycin scaffold as a privileged starting point for the discovery of novel TB drug leads. In this manuscript we describe the rapid synthesis of a library of sansanmycin analogues that exhibit potent and selective activity against the virulent H37Rv strain of Mtb
We show that these natural product analogues disrupt the activity of Mtb phospho-MurNAc-pentapeptide translocase, the integral membrane enzyme responsible for the biosynthesis of lipid I, a key intermediate in mycobacterial peptidoglycan synthesis

Summary

Introduction

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. A number of alkyl, heteroalkyl, aryl and heteroaryl substituents were proposed in analogues [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36] with a view to interrogating further SARs. Dihydrosansanmycin analogues [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36] were synthesized using the divergent solid-phase strategy described above (Supplementary Methods) and assessed for anti-mycobacterial activity against Mtb H37Rv (Fig. 3).

Results

Conclusion