ADP-ribosylation has been known to play a significant role in both eukaryotic and prokaryotic biology. A small ADP-ribosyltransferase (ART) called Arr is encoded by both Gram-positive and -negative pathogens, which confers resistance against the rifamycin family of antibiotics via modification. In our study we found Mycobaterium smegmatis (Msm) encodes a C-terminal region of Arr (ArrC) along with a full-length version, which can promote activity of Arr. Based on the structural similarity between Msm Arr and human PARP-1, we reasoned that known hPARP-1 inhibitors might serve as Arr inhibitors. We identified known PARP-1 inhibitors that show moderate inhibition against Msm Arr (mid-micromolar IC50). In vivo, a select PARP inhibitor can sensitize Msm to rifampin (reducing the MIC 50 from 5.14 μg/mL to 0.718 μg/mL), which is associated with the existence of arr in Msm genome. M. abscessus, a major multi-drug resistant non-tuberculosis mycobacterial pathogen, also contains a rifampin ART (Mab_0591). Arr inhibition also reduces the MIC50 of rifampin in M. abscessus from 6.65 μg/mL to &lt;1 μg/mL in the presence of the PARP inhibitor, which provides promising combination treatment to this emerging pathogen.

Modulation of bacterial ADP-ribosyltransferase – fighting against rifamycin resistance and beyond

ACS Spring 2022

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