Identification of a novel ltaS mutation in daptomycin heteroresistant community-acquired methicillin-resistant Staphylococcus aureus ST72 strains in South Korea

Daptomycin has been used globally since 2003, with a corresponding increase in daptomycin nonsusceptible (DNS) Staphylococcus aureus. In South Korea, daptomycin became available in 2020, but emerging resistance has posed early therapeutic challenges. We observed suspected heteroresistance to daptomycin (h-DAP) in community-acquired methicillin-resistant S. aureus (CA-MRSA) isolates from a patient who experienced recurrent bacteremia during high-dose daptomycin treatment for MRSA bacteremic pyogenic spondylodiscitis. Phenotypic and genotypic analyses were performed on 15 sequential isolates collected before, during, and after daptomycin therapy. Population analysis profiling confirmed DNS in three isolates obtained during therapy, which reverted phenotypically to susceptibility following treatment cessation. Whole-genome sequencing of a susceptible and nonsusceptible isolate pair revealed that both belonged to the Korean CA-MRSA clone (ST72, spa type t4359, SCCmec IVc) and harbored multiple mprF mutations not matching known DNS-associated variants. Notably, a unique mutation in ltaS (A1744T; N582Y) was identified, which has not been previously reported in NCBI databases. The role of ltaS in mediating reversible DNS under daptomycin exposure warrants further functional investigation. As bacteremia caused by the ST72 CA-MRSA clone continues to rise in South Korea, the emergence of h-DAP in this strain may compromise daptomycin efficacy. Ongoing surveillance of DNS is therefore essential.