Rifamycin congeners kanglemycins are active against rifampicin-resistant bacteria via a distinct mechanism

James Peek, Mirjana Lilic, Daniel Montiel, Aleksandr Milshteyn, Ian Woodworth, John B. Biggins, Melinda A. Ternei, Paula Y. Calle, Michael Danziger, Thulasi Warrier, Kohta Saito, Nathaniel Braffman, Allison Fay, Michael S. Glickman, Seth A. Darst, Elizabeth A. Campbell () and Sean F. Brady ()
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James Peek: The Rockefeller University
Mirjana Lilic: The Rockefeller University
Daniel Montiel: The Rockefeller University
Aleksandr Milshteyn: The Rockefeller University
Ian Woodworth: The Rockefeller University
John B. Biggins: The Rockefeller University
Melinda A. Ternei: The Rockefeller University
Paula Y. Calle: The Rockefeller University
Michael Danziger: The Rockefeller University
Thulasi Warrier: Weill Cornell Medicine
Kohta Saito: Weill Cornell Medicine
Nathaniel Braffman: The Rockefeller University
Allison Fay: Sloan-Kettering Institute
Michael S. Glickman: Sloan-Kettering Institute
Seth A. Darst: The Rockefeller University
Elizabeth A. Campbell: The Rockefeller University
Sean F. Brady: The Rockefeller University

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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 (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 RifR mutations. Our structural and mechanistic analyses reveal the basis for Kang inhibition of RifR 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.

Date: 2018
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DOI: 10.1038/s41467-018-06587-2

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