Reversion of antibiotic resistance by inhibiting mecA in clinical methicillin-resistant Staphylococci by antisense phosphorothioate oligonucleotide.

Abstract

Methicillin-resistant Staphylococci (MRS), methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE) have become a challenging problem in nosocomial infections and are connected with high morbidity and mortality rates. This is due to the increasing incidence of resistance to virtually all β-lactams and a wide variety of antimicrobials. The spread of MRS severely limits therapeutic options and generates the need for novel antibiotics that are able to combat MRS infections. One method of inhibiting bacterial growth is by blocking the expression of conserved bacterial genes and provides potential new avenues for generating a new generation of antimicrobials. The mecA gene is highly conserved among Staphylococcal species, and this makes it an ideal target for antisense inhibition. We had identified a target sequence (854-871 nt) within the mecA mRNA coding region that is particularly sensitive to antisense inhibition. The anti-mecA PS-ODN04 oligonucleotide was encapsulated into an anionic liposome. MRSA01 and MRSE01 clinical strains treated with this antisense sequence became susceptible to existing β-lactam antibiotics, and their growth was inhibited by oxacillin in vitro and in vivo. PS-ODN04 reduced the bacterial titers in the blood of mice infected with MRSA01 and MRSE01 and significantly improved their survival rate. Our data offer a possible new strategy for treating MRS infections.