Angucyclinones rescue PhLOPSA antibiotic activity by inhibiting Cfr-dependent antibiotic resistance.

IMPORTANCE: Cfr is an antibiotic resistance enzyme that inhibits five clinically important antibiotic classes, is genetically mobile, and has a minimal fitness cost, making Cfr a serious threat to antibiotic efficacy. The significance of our work is in discovering molecules that inhibit Cfr-dependent methylation of the ribosome, thus protecting the efficacy of the PhLOPSA antibiotics. These molecules are the first reported inhibitors of Cfr-mediated ribosome methylation and, as such, will guide the further discovery of chemical scaffolds against Cfr-mediated antibiotic resistance. Our work acts as a foundation for further development of molecules that safeguard the PhLOPSA antibiotics from Cfr.