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Mode of Action of Kanglemycin A, an Ansamycin Natural Product that Is Active against Rifampicin Resistant Mycobacterium tuberculosis

Lookup NU author(s): Dr Hamed Mosaei Sejzi, Dr Bernhard Kepplinger, John Harbottle, Lucia Ceccaroni Ceccaroni, Dr Stephanie Morton-Laing, Dr Corinne Wills, Professor William Clegg, Dr Yulia Yuzenkova, Dr John Perry, Professor Jeff ErringtonORCiD, Dr Nicholas Allenby, Dr Michael HallORCiD, Professor Nikolay ZenkinORCiD

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This is the final published version of an article that has been published in its final definitive form by Cell Press, 2018.

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Abstract

Antibiotic resistant bacterial pathogens pose an urgent healthcare threat,prompting a demand for new medicines. We report the mode of action of the natural ansamycin antibiotic kanglemycin A(KglA). KglA binds bacterial RNA polymerase at the rifampicin-binding-pocket, but maintains potency against RNA polymerases containing rifampicin-resistant mutations.KglAhas antibiotic activity against rifampicin-resistant Gram-positive bacteria and multidrug-resistant Mycobacterium tuberculosis(MDR-M. tuberculosis). X-ray crystal structures of KglA with Escherichia coli RNA polymerase holoenzyme and Thermusthermophilus RNA polymerase-promoter complexreveal an altered, as compared to rifampicin, conformation of KglA within the rifampicin-binding pocket. Unique deoxysugar and succinate ansa-bridge substituents make additional contacts with a separate hydrophobic pocket of RNA polymerase and preclude the formation of initial tetraphosphate-dinucleotide, respectively. Previous ansa-chain modifications in the rifamycin series has proven unsuccessful. Thus KglA represents a key starting point for the development a new class of ansa-chain derivatized ansamycins to tackle rifampicin-resitance.

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Author(s): Mosaei H, Molodtsov V, Kepplinger B, Harbottle J, Moon C, Jeeves R, Ceccaroni L, Shin Y, Morton-Laing S, Marrs ECL, Wills C, Clegg W, Yuzenkova J, Perry JD, Bacon J, Errington J, Allenby NEE, Hall MJ, Murakami KS, Zenkin N

Publication type: Article

Publication status: Published

Journal: Molecular Cell

Year: 2018

Volume: 72

Issue: 2

Pages: 263-274

Print publication date: 18/10/2018

Online publication date: 20/09/2018

Acceptance date: 17/08/2018

Date deposited: 25/09/2018

ISSN (print): 1097-2765

ISSN (electronic): 1097-4164

Publisher: Cell Press

URL: https://doi.org/10.1016/j.molcel.2018.08.028

DOI: 10.1016/j.molcel.2018.08.028

Notes: Mosaei H, Molodtsov V, Kepplinger B all contributed equally

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