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

Hamed Mosaei, Vadim Molodtsov, Bernhard Kepplinger, John Harbottle, Christopher William Moon, Rose Elizabeth Jeeves, Lucia Ceccaroni, Yeonoh Shin, Stephanie Morton-Laing, Emma Claire Louise Marrs, Corinne Wills, William Clegg, Yulia Yuzenkova, John David Perry, Joanna Bacon, Jeff Errington, Nicholas Edward Ellis Allenby, Michael John Hall, Katsuhiko S. Murakami*, Nikolay Zenkin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

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. KglA has antibiotic activity against rifampicin-resistant Gram-positive bacteria and multidrug-resistant Mycobacterium tuberculosis (MDR-M. tuberculosis). The X-ray crystal structures of KglA with the Escherichia coli RNA polymerase holoenzyme and Thermus thermophilus RNA polymerase-promoter complex reveal an altered—compared with 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 dinucleotides, respectively. Previous ansa-chain modifications in the rifamycin series have proven unsuccessful. Thus, KglA represents a key starting point for the development of a new class of ansa-chain derivatized ansamycins to tackle rifampicin resistance. Resistance to rifamycins, inhibitors of bacterial RNA polymerase used for treatment of tuberculosis, is increasing. Mosaei et al. report an analog of the rifamycins, kanglemycin A, that inhibits rifampicin-resistant RNA polymerases and is effective against multidrug-resistant M. tuberculosis, and they describe its mechanism of action.

Original languageEnglish
Pages (from-to)263-274.e5
JournalMolecular Cell
Volume72
Issue number2
DOIs
Publication statusPublished - 18 Oct 2018

Bibliographical note

Funding Information:
We thank the staff at the MacCHESS for support with crystallographic data collection. We also thank UK Engineering and Physical Sciences Research Council for X-ray crystallography facilities (grant EP/F03637X/1), Dr U. Baisch (Newcastle University) for measuring the CuKalpha diffraction data, Diamond Light Source for access to beamline I19 (award MT8682), Prof. W. McFarlane (Newcastle University) for NMR support, and Dr. J. Gray (Newcastle University) for HRMS analysis. We acknowledge the PHE National Mycobacterium Reference Laboratory (NMRL) for providing M. tuberculosis Beijing strains 1192/015 and 08/00483E. This work was supported by Wellcome Trust Investigator Award 102851 and Leverhulme Trust Prize PLP-2014-229 (to N.Z.), Innovate UK grants 100953 and 131143 (to N.E.E.A.), a Royal Society University Research Fellowship (to Y.Y.), NIH grant GM087350 (to K.S.M.), a Department of Health Grant in Aid and The PHE Pipeline Fund (to J.B.; the views expressed in this publication are those of the authors and not necessarily those of Public Health England or the Department of Health), and UK Medical Research Council studentship MR/N018613/1 (to J.H.).

Funding Information:
We thank the staff at the MacCHESS for support with crystallographic data collection. We also thank UK Engineering and Physical Sciences Research Council for X-ray crystallography facilities (grant EP/F03637X/1 ), Dr U. Baisch (Newcastle University) for measuring the CuKalpha diffraction data, Diamond Light Source for access to beamline I19 (award MT8682), Prof. W. McFarlane (Newcastle University) for NMR support, and Dr. J. Gray (Newcastle University) for HRMS analysis. We acknowledge the PHE National Mycobacterium Reference Laboratory (NMRL) for providing M. tuberculosis Beijing strains 1192/015 and 08/00483E. This work was supported by Wellcome Trust Investigator Award 102851 and Leverhulme Trust Prize PLP-2014-229 (to N.Z.), Innovate UK grants 100953 and 131143 (to N.E.E.A.), a Royal Society University Research Fellowship (to Y.Y.), NIH grant GM087350 (to K.S.M.), a Department of Health Grant in Aid and The PHE Pipeline Fund (to J.B.; the views expressed in this publication are those of the authors and not necessarily those of Public Health England or the Department of Health), and UK Medical Research Council studentship MR/N018613/1 (to J.H.).

Publisher Copyright:
© 2018 The Authors

Keywords

  • MDR-TB
  • RNA polymerase
  • antibiotic resistance
  • antibiotics
  • holo-enzyme crystal structure
  • kanglemycin A
  • multidrug-resistant Mycobacterium tuberculosis
  • promoter complex crystal structure
  • rifampicin
  • rifamycin

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