As a result of the continual rise in infections caused by multi-resistant bacteria, modern medicine increasingly relies on reserve antibiotics. Accordingly, the emerging resistance to these drugs poses a serious health risk. Daptomycin (DAP) is a lipopeptide antibiotic classified as a reserve antibiotic for treating infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Clinical treatment failure and DAP resistance remain rare and have been associated with adaptive chromosomal mutations. However, they have not been linked to the acquisition of specific resistance traits. The Mammaliicoccus sciuri strain TS92 was previously found to display an unprecedentedly high DAP resistance level, which, however, is not linked to known mutations. This thesis aimed to elucidate the genetic and molecular background of the DAP resistance phenotype of the isolate. Transcription profiling and mutational analysis of candidate genes identified a two-gene operon (named drcAB; daptomycin resistance cluster) controlled by an adjacent two-component system (drcRS) as the underlying mechanism of DAP resistance. The membrane-associated Drc proteins exhibit homologies to Bce-like ABC transporters, which are typically involved in antimicrobial peptide defence, yet are distinct from known systems. The DrcAB complex was found to possess transferase and hydrolase activities that lead to DAP inactivation by chemical modification. The drc locus is not part of the core genome of M. sciuri species but was acquired by strain TS92 through horizontal gene transfer (HGT). Notably, drc is fully functional in various Gram-positive bacterial backgrounds, including clinically relevant MRSA. Database research revealed that the locus is mobile and detectable in commensal staphylococcal and enterococcal isolates from livestock and in apathogenic Gram-positive bacteria from the human gut microbiota and the environment. Bioinformatic analyses suggest that the ancestral species of drc is most likely an unidentified Gram-positive bacterium from the environment. This study reports, for the first time, an acquired DAP resistance mechanism circulating among commensal and low-pathogenic bacteria, indicating the risk of drc transmission also to MRSA and other pathogens. Finally, the data highlight the importance of low-pathogenic and environmental microorganisms as potent but still underestimated reservoirs of resistance determinants for pathogens. Consequently, and in line with the modern One Health concept, these bacteria should be included in existing surveillance systems for antimicrobial resistance.
Tessa Marciniak (Thu,) studied this question.