Molecular basis and evolutionary cost of a novel phenotype of macrolides/lincosamides resistance in Staphylococcus haemolyticus

Staphylococcus haemolyticus ( S. haemolyticus ) is a coagulase-negative Staphylococcus and has become one of the primary pathogens of nosocomial infections. After a long period using the antibiotics against the infections caused by S. haemolyticus, S. haemolyticus developed several resistance phenotypes of macrolides and lincosamides. Here, we acquired four S. haemolyticus clinical isolates, of which three isolates demonstrated antibiotic resistance as reported previously, while one was resistant to both erythromycin and clindamycin without erythromycin induction. Such novel phenotype, known as constitutive Macrolides-Lincosamides-Streptogramins (MLS) resistance, was reported in other bacteria, but it was found for the first time in S. haemolyticus . To further investigate such behavior, we confirmed that the deletion of the methyltransferase ErmC upstream leader peptide was critical to cause constitutive MLS resistance based on the analysis of potential antibiotic resistance genes via whole-genome sequencing and experimental verification. In addition, we discovered that the continuous expression of ErmC may inhibit the growth of S. haemolyticus , which turned out to be the cost with no MLS pressure. Taken together, this study firstly reported the constitutive MLS resistance in S. haemolyticus , and provided new ideas for using macrolides and lincosamides in clinical treatment. ### Competing Interest Statement The authors have declared no competing interest.