Effect of Staphylococcus aureus Tet38 native efflux pump on in vivo response to tetracycline in a murine subcutaneous abscess model

Staphylococcus aureus native efflux pump Tet38 confers resistance to tetracycline when overexpressed. tet38 expression is selectively upregulated in infection sites. This study evaluated the effect of Tet38 on tetracycline response in a murine subcutaneous abscess model. S. aureus MW2 and its tet38 mutant were injected subcutaneously on the opposite flanks of each mouse. The infected mice were treated with tetracycline (10 mg/kg) or PBS (control) intraperitoneally every 12 h. The efficacy of tetracycline against S. aureus was measured by the relative change in viable bacteria in the abscesses 24 h after infection compared with the initial inoculum. Plasmid-based tet38-complemented strains were created and used to infect the mice followed by tetracycline or PBS treatment. The increased bacterial loads of S. aureus MW2 and its tet38 mutant in the abscess after 24 h were similar. Tetracycline produced significant decreases of both MW2 and the tet38 mutant compared with control. Although the tetracycline MICs for MW2 and the tet38 mutant did not differ in vitro, the antibacterial effect of tetracycline was significantly 2-fold greater in the tet38 mutant compared with the MW2 parental strain in vivo with a decrease of 0.67aY +/- aY0.21 and 0.35aY +/- aY0.19 log(10) cfu/abscess, respectively (P < 0.05). The increased tetracycline activity in the tet38 mutant was complemented by plasmid-encoded tet38. This study demonstrated that selective increased expression of tet38 in an abscess can affect tetracycline efficacy against S. aureus in vivo, highlighting an effect of native efflux pumps on response to therapy not reflected by testing in vitro.