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

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

Molecular cell (2018-09-25)
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
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.

MATERIALS
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Product Description

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