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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
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.
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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