Modulation of a Mycobacterial ADP-Ribosyltransferase to Augment Rifamycin Antibiotic Resistance

The rifamycins are broad-spectrum antibiotics that are primarily utilized to treat infections caused by mycobacteria, including tuberculosis. Interestingly, various species of bacteria are known to contain an enzyme called Arr that catalyzes ADP-ribosylation of rifamycin antibiotics as a mechanism of resistance. Here, we study Arr modulation in relevant Gram-positive and -negative species. We show that a C-terminal truncation of Arr (ArrC), encoded in the genome of Mycobacterium smegmatis, activates Arr-mediated rifamycin modification. Through structural comparisons of mycobacterial Arr and human poly(ADP-ribose) polymerases (PARPs), we identify a known small molecule PARP inhibitor that can act as an adjuvant to sensitize M. smegmatis to the rifamycin antibiotic rifampin via inhibition of Arr, even in the presence of ArrC. Finally, we demonstrate that this rifampin/adjuvant combination treatment is effective at inhibiting growth of the multidrug-resistant (MDR) nontuberculosis pathogen Mycobacterium abscessus, which has become a growing cause of human infections in the clinic.