Abstract
BlaI is a repressor of BlaZ, the beta-lactamase responsible for penicillin resistance in Staphylococcus aureus. Through screening a transposon library in S. aureus Newman for susceptibility to cathelicidin antimicrobial peptide, we discovered BlaI as a novel cathelicidin resistance factor. Additionally, through integrational mutagenesis in S. aureus Newman and MRSA Sanger 252 strains, we confirmed the role of BlaI in resistance to human and murine cathelidicin and showed that it contributes to virulence in human whole blood and murine infection models. We further demonstrated that BlaI could be a target for innate immune-based antimicrobial therapies; by removing BlaI through subinhibitory concentrations of 6-aminopenicillanic acid, we were able to sensitize S. aureus to LL-37 killing.
Highlights
Staphylococcus aureus is a leading cause of community- and hospital-associated infections, ranging from superficial syndromes to several potentially life-threatening invasive conditions including sepsis and endocarditis [1]
To identify staphylococcal genes involved in cathelicidin resistance, a random mutant library of S. aureus Newman was generated by Tn917 transposition
Putative CRAMP susceptible mutants identified in the primary screen were subjected to additional testing to confirm their phenotype by characterizing (i) their susceptibility to CRAMP in exponential and stationary phase and (ii) by demonstrating that the mutants exhibited no replication defects in growth curves compared to the WT strain in Todd Hewitt broth (THB; data not shown)
Summary
Staphylococcus aureus is a leading cause of community- and hospital-associated infections, ranging from superficial syndromes to several potentially life-threatening invasive conditions including sepsis and endocarditis [1]. Penicillin was once the drug of choice for treatment of S. aureus infections. Penicillin-resistant strains due to beta-lactamase production were reported as early as 1942, and today over 95% of human S. aureus isolates are resistant to penicillin [2]. The beta-lactamase-resistant penicillin derivate methicillin was introduced in 1961, but the first methicillin-resistant S. aureus (MRSA) strains appeared shortly thereafter. Recent reports of S. aureus isolates with intermediate or complete vancomycin resistance may foreshadow an era in which effective treatment of S. aureus infections may become extraordinarily.
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