SNAP output for PDB entry 6dcf [SNAP web server]

PDB-id

6dcf; SNAP-derived features in text and JSON formats; DNAproDB

Class

transcription-DNA-antibiotic

Method

X-ray (3.45 Å)

Summary

Crystal structure of a mycobacterium smegmatis transcription initiation complex with rifampicin-resistant RNA polymerase and bound to kanglemycin a

Reference

Peek J, Lilic M, Montiel D, Milshteyn A, Woodworth I, Biggins JB, Ternei MA, Calle PY, Danziger M, Warrier T, Saito K, Braffman N, Fay A, Glickman MS, Darst SA, Campbell EA, Brady SF (2018): "Rifamycin congeners kanglemycins are active against rifampicin-resistant bacteria via a distinct mechanism." Nat Commun, 9, 4147. doi: 10.1038/s41467-018-06587-2.

Abstract

Rifamycin antibiotics (Rifs) target bacterial RNA polymerases (RNAPs) and are widely used to treat infections including tuberculosis. The utility of these compounds is threatened by the increasing incidence of resistance (Rif_R). As resistance mechanisms found in clinical settings may also occur in natural environments, here we postulated that bacteria could have evolved to produce rifamycin congeners active against clinically relevant resistance phenotypes. We survey soil metagenomes and identify a tailoring enzyme-rich family of gene clusters encoding biosynthesis of rifamycin congeners (kanglemycins, Kangs) with potent in vivo and in vitro activity against the most common clinically relevant Rif_R mutations. Our structural and mechanistic analyses reveal the basis for Kang inhibition of Rif_R RNAP. Unlike Rifs, Kangs function through a mechanism that includes interfering with 5'-initiating substrate binding. Our results suggest that examining soil microbiomes for new analogues of clinically used antibiotics may uncover metabolites capable of circumventing clinically important resistance mechanisms.