Nationwide dalbavancin surveillance identifies sagB-associated cell-wall adaptation linked to reduced lipoglycopeptide susceptibility in CC5 Staphylococcus aureus.

AIMS: Dalbavancin is a long-acting lipoglycopeptide with potent activity against Staphylococcus aureus. However, the emergence of reduced dalbavancin susceptibility and its underlying molecular mechanisms remain poorly understood.

METHODS

Dalbavancin MICs were determined for 1803 S. aureus isolates from 37 hospitals in 27 provinces of China. Comparative genomics of a clinical dalbavancin-nonsusceptible (DAL-NS) isolate and in vitro vancomycin-selected derivatives was performed to identify resistance-associated mutations. The role of sagB was assessed by gene deletion and complementation, followed by antimicrobial susceptibility testing and phenotypic assays. Transcriptomic profiling, autolysis assays, electron microscopy, cytochrome c binding assays, and time-kill assays were performed to characterize the cellular effects of sagB dysfunction.

RESULTS

Dalbavancin showed potent activity, with MIC50/MIC90 values of 0.06/0.125 μg/mL, and only one nonsusceptible isolate was detected (0.06%, 1/1803). This isolate belonged to ST5523/CC5 and had prior vancomycin exposure but no dalbavancin treatment. sagB mutations occurred in both the clinical isolate and independent vancomycin-selected derivatives with reduced dalbavancin susceptibility. Genetic complementation and deletion supported sagB dysfunction as contributing to reduced susceptibility to lipoglycopeptides, glycopeptides, and lipopeptides, with reciprocal β-lactam sensitization. Mechanistically, sagB dysfunction altered cell-wall hydrolase expression, autolysis, and envelope properties, and was associated with prolonged survival under dalbavancin exposure but enhanced killing by oxacillin.

CONCLUSIONS

Dalbavancin remains highly active against clinical S. aureus in China. Rare nonsusceptibility may emerge under glycopeptide pressure through lineage-conditioned sagB-associated cell-wall remodeling.