6DCF

Crystal structure of a Mycobacterium smegmatis transcription initiation complex with Rifampicin-resistant RNA polymerase and bound to kanglemycin A

Summary for 6DCF

• Entry DOI: 10.2210/pdb6dcf/pdb
• Descriptor: RNA polymerase-binding protein RbpA, SULFATE ION, ZINC ION, ... (15 entities in total)
• Functional Keywords: inhibitor, complex, rna polymerase, transcription-dna-antibiotic complex, transcription/dna/antibiotic
• Biological source: Mycobacterium smegmatis (strain ATCC 700084 / mc(2)155); More
• Total number of polymer chains: 9
• Total formula weight: 447307.40

Authors

Lilic, M.,Darst, S.A.,Campbell, E.A. (deposition date: 2018-05-06, release date: 2018-09-05, Last modification date: 2023-10-11)

Primary citation

Peek, J.,Lilic, M.,Montiel, D.,Milshteyn, A.,Woodworth, I.,Biggins, J.B.,Ternei, M.A.,Calle, P.Y.,Danziger, M.,Warrier, T.,Saito, K.,Braffman, N.,Fay, A.,Glickman, M.S.,Darst, S.A.,Campbell, E.A.,Brady, S.F.
Rifamycin congeners kanglemycins are active against rifampicin-resistant bacteria via a distinct mechanism.
Nat Commun, 9:4147-4147, 2018

PubMed 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). 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 mutations. Our structural and mechanistic analyses reveal the basis for Kang inhibition of Rif 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.

PubMed: 30297823
DOI: 10.1038/s41467-018-06587-2

Experimental method

X-RAY DIFFRACTION (3.45 Å)