1区 · 生物学
Article
作者: Hall, Michael John ; Errington, Jeff ; Mosaei, Hamed ; Perry, John David ; Moon, Christopher William ; Harbottle, John ; Allenby, Nicholas Edward Ellis ; Zenkin, Nikolay ; Yuzenkova, Yulia ; Jeeves, Rose Elizabeth ; Bacon, Joanna ; Kepplinger, Bernhard ; Marrs, Emma Claire Louise ; Ceccaroni, Lucia ; Morton-Laing, Stephanie ; Molodtsov, Vadim ; Murakami, Katsuhiko S ; Shin, Yeonoh ; Wills, Corinne ; Clegg, William
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.
