Resistance-guided mining of bacterial genotoxins defines a family of DNA glycosylases [article]

Noah P Bradley, Katherine L Wahl, Jacob L Steenwyk, Antonis Rokas, Brandt F. Eichman
2021 bioRxiv   pre-print
Unique DNA repair enzymes that provide self-resistance against genotoxic natural products have been discovered recently in bacterial biosynthetic gene clusters (BGCs). The DNA glycosylase AlkZ belongs to a superfamily of uncharacterized proteins found in antibiotic producers and pathogens, but despite its importance to azinomycin B resistance, the roles of AlkZ orthologs in production of other natural products are unknown. Here, we analyze the genomic distribution and use a resistance-based
more » ... me mining approach to identify Streptomyces AlkZ homologs associated with known and uncharacterized BGCs. We show that the ortholog associated with synthesis of the alkylating agent hedamycin excises hedamycin-DNA adducts and provides resistance to the genotoxin in cells. Our results define AlkZ in self-resistance to specific antimicrobials and implicate a related but distinct homolog, which we name AlkX, in protection against an array of genotoxins. This work provides a framework for targeted discovery of new genotoxic compounds with therapeutic potential.
doi:10.1101/2021.10.29.466481 fatcat:fpwzs5g5z5h6vnetzp74rj3mwe