NucS Thr74Ile confers mutator phenotype in a globally disseminated clinical Mycobacterium abscessus subsp. abscessus...

The emergence of mutations conferring resistance to first-line drugs, macrolides and amikacin, is a major cause of treatment failure in Mycobacterium abscessus complex (MABC) infections; however, mutator strains predisposed to developing drug-resistance mutations remain uncharacterized. NucS, a key DNA mismatch repair protein, maintains mycobacterial genomic stability. This study investigated whether naturally occurring NucS polymorphisms contribute to mutator phenotypes in clinical MABC strains.

The whole genome data of clinical MABC isolates obtained from public databases were analysed to identify naturally occurring NucS polymorphisms. Phylogenetic analysis was performed to elucidate the relationship between the common NucS Thr74Ile polymorphism and drug resistance mutations. The effects of polymorphisms on NucS activity were analysed by checking their impact on mutation rates of drug resistance using a M. abscessus subsp. abscessus (Mabs) homologous system.

Seven NucS polymorphisms were identified. Notably, the Mabs (the most prevalent MABC subspecies) nucS C221T/erm(41) T28C isolates belong to a globally disseminated clone. These drug-sensitive strains exhibit heightened potential for acquired resistance to macrolides and amikacin conferred by rrl and rrs mutations, respectively, and some restore inducible macrolide-resistance by reverting to wild-type erm(41) T28 through evolutionary descent. The NucS Thr74Ile (c.C221T) polymorphism was identified as a key driver of this process in the Mabs homologous system.

These findings highlight the existence of globally disseminated clinical Mabs mutator clone with a potential increase in drug-resistance mutations affected by NucS Thr74Ile polymorphism, indicating an urgent need for novel therapies and enhanced community surveillance.