Rifamycin congeners kanglemycins are active against rifampicin-resistant bacteria via a distinct mechanism Academic Article uri icon

Overview

MeSH Major

  • Adolescent Behavior
  • Condoms
  • HIV Infections
  • Health Knowledge, Attitudes, Practice
  • Safe Sex

abstract

  • © 2018, The Author(s). 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 (RifR). 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 RifRmutations. Our structural and mechanistic analyses reveal the basis for Kang inhibition of RifRRNAP. 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.

publication date

  • December 2018

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC6175910

Digital Object Identifier (DOI)

  • 10.1038/s41467-018-06587-2

PubMed ID

  • 30297823

Additional Document Info

start page

  • 4147

volume

  • 9

number

  • 1