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Arr is an ADP-ribosyltransferase enzyme primarily reported in association with rifamycin resistance, which has been used to treat tuberculosis in addition to Gram-positive infections and, recently, pan-resistant Gram-negative bacteria. The  arr  gene was initially identified on the  Mycolicibacterium smegmatis  chromosome and later on  Proteobacteria  plasmids. This scenario raised concerns on the distribution and spread of  arr , considering the Bacteria domain. Based on 198,082 bacterial genomes/metagenomes, we performed in silico analysis, including phylogenetic reconstruction of Arr in different genomic contexts. Besides, new  arr  alleles were evaluated by in vitro analysis to assess their association with rifampin resistance phenotype. The  arr  gene was prevalent in thousands of chromosomes and in hundreds of plasmids from environmental and clinical bacteria, mainly from the phyla  Actinobacteria ,  Proteobacteria ,  Firmicutes , and  Bacteroidetes . Furthermore, this gene was identified in other and new genomic contexts. Interestingly, Arr sequences associated with rifampin resistance were distributed across all phylogeny, indicating that, despite the diversity, their association with rifampin resistance phenotype were maintained. In fact, we found that the key residues were highly conserved. In addition, other analyzes have raised evidence of another Arr function, which is related to guanidine metabolism. Finally, this scenario as a whole also suggested the  Actinobacteria  phylum as a potential ancestral source of  arr  within the Bacteria domain.

Genomic epidemiology of rifampicin ADP-ribosyltransferase (Arr) in the Bacteria domain