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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, Emeritus Professor Bill CleggORCiD, Dr Yulia Yuzenkova, Dr John Perry, Professor Jeff ErringtonORCiD, Dr Nicholas Allenby, Dr Michael HallORCiD, Professor Nikolay ZenkinORCiD



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

For re-use rights please refer to the publisher's terms and conditions.


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.

Publication metadata

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


DOI: 10.1016/j.molcel.2018.08.028

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


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Funder referenceFunder name
Wellcome Trust