Rifamycins, such as rifampicin, are potent inhibitors of bacterial RNA polymerases and widely used antibiotics. Usually rifamycin-resistance is associated with mutations in RNAP that preclude rifamycins binding. However, some bacteria have ADP-ribosyl transferases Arr that ADP-ribosylate rifamycin molecules, thus inactivating their antimicrobial activity. Here we directly show that ADP-ribosylation abolishes inhibition of transcription by rifampicin, the most widely used rifamycin antibiotic. We also show that natural rifamycin, Kanglemycin A, which has a unique sugar moiety at the ansa-chain close to the Arr-modification site, does not bind to Arr from
M. smegmatis
, and thus is not susceptible to inactivation. We, however, found that Kanglemycin A can still be ADP-ribosylated by Arr of an emerging pathogen
M. abscessus
. Interestingly, the only part of Arr which exhibits no homology between the species is the part that sterically clashes with sugar moiety of Kanglemycin A in
M. smegmatis
Arr. This suggests that
M. abscessus
has encountered KglA or rifamycin with similar sugar modification in the course of evolution. The results show that KglA could be effective antimicrobial against some of the Arr encoding bacteria.
Conserved functions of the trigger loop and Gre factors in RNA cleavage by bacterial RNA polymerases
