Pathogen-encoded Rum DNA polymerase drives rapid bacterial drug resistance.

The acquisition of multidrug resistance by pathogenic bacteria is a potentially incipient pandemic. Horizontal transfer of DNA from mobile integrative conjugative elements (ICEs) provides an important way to introduce genes that confer antibiotic (Ab)-resistance in recipient cells. Sizable numbers of SXT/R391 ICEs encode a hypermutagenic Rum DNA polymerase (Rum pol), which has significant homology with E. coli pol V. Here, we show that when under tight, environmentally relevant, transcriptional and post-transcriptional regulation, Rum pol drives rapid multidrug resistance in E. coli in response to SOS-inducing Ab and non-Ab external stressors bleomycin (BLM) and UV radiation. The impact of Rum pol on the rate of drug resistance appears to surpass potential contributions from other cellular processes. We have shown that RecA protein plays a central role in controlling the ability of Rum pol to generate drug resistance. A single amino acid substitution in RecA M197D acts as a Master Regulator that effectively eliminates the Rum pol-induced Ab resistance. We suggest that Rum pol should be considered as one of the major factors driving development of de novo antibiotic resistance in pathogens carrying R391 SXT/ICEs