Induction of clpP expression by cell-wall targeting antibiotics in Streptococcus mutans

Abstract

Streptococcus mutansis one of the major bacteria of the human oral cavity that is associated with dental caries. The pathogenicity of this bacterium is attributed to its ability to rapidly respond and adapt to the ever-changing conditions of the oral cavity. The major player in this adaptive response is ClpP, an intracellular protease involved in degradation of misfolded proteins during stress responses.S. mutansencodes a singleclpPgene with an upstream region uniquely containing multiple tandem repeat sequences (RSs). Here, we explored expression ofclpPwith respect to various stresses and report some new findings. First, we found that at sub-inhibitory concentration, certain cell-wall damaging antibiotics were able to induceclpPexpression. Specifically, third- and fourth-generation cephalosporins that target penicillin-binding protein 3 (PBP3) strongly enhanced theclpPexpression. However, induction ofclpPwas weak when the first-generation cephalosporins with lower affinity to PBP3 were used. Surprisingly, carbapenems, which primarily target PBP2, induced expression ofclpPthe least. Second, we found that a single RS element was capable of inducingclpPexpression as efficiently as with the wild-type seven RS elements. Third, we found that the RS-element-mediated modulation ofclpPexpression was strain dependent, suggesting that specific host factors might be involved in the transcription. And finally, we observed that ClpP regulates its own expression, as the expression ofclpP-gusAwas higher in aclpP-deficient mutant. This suggests that ClpP is involved in the degradation of activator(s) involved in its own transcription.