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Mode of Action of Kanglemycin A, an Ansamycin Natural Product that Is Active against Rifampicin-Resistant Mycobacterium tuberculosis
- Mosaei, Hamed, Molodtsov, Vadim, Kepplinger, Bernhard, Harbottle, John, Moon, Christopher William, Jeeves, Rose Elizabeth, Ceccaroni, Lucia, Shin, Yeonoh, Morton-Laing, Stephanie, Marrs, Emma Claire Louise, Wills, Corinne, Clegg, William, Yuzenkova, Yulia, Perry, John David, Bacon, Joanna, Errington, Jeff, Allenby, Nicholas Edward Ellis, Hall, Michael John, Murakami, Katsuhiko S., Zenkin, Nikolay
- Molecular cell 2018 v.72 no.2 pp. 263-274.e5
- DNA-directed RNA polymerase, Escherichia coli, Gram-positive bacteria, Mycobacterium tuberculosis, RNA, Thermus thermophilus, antibacterial properties, antibiotic resistance, crystal structure, health services, hydrophobicity, mechanism of action, multiple drug resistance, mutation, pathogens, rifampicin
- 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.