Acid adaptation alters Streptococcus mutans drug susceptibility profile

Abstract

The ability of Streptococcus mutans, the primary causative agent of dental caries, to generate and tolerate an acidic environment is a leading factor in its capacity to outcompete other organisms within the oral cavity. The acid tolerance response (ATR) involves coordination of multiple pathways to upregulate macromolecule repair, maintenance of cytosolic pH, and restructuring the membrane. In this study, we asked if the changes associated with adaptation to a low pH environment would result in detectable changes to drug susceptibility. Accordingly, we screened using the Selleck library of 853 FDA approved drugs for agents that exhibit antimicrobial activity toward planktonic cultures of S. mutans or disrupt biofilm formation in growth medium titrated to pH 5 or in the presence of hydrogen peroxide. Results revealed that a total of 182 compounds displayed antimicrobial properties toward the test strain in at least one screening condition. Our findings provide evidence that the S. mutans ATR is characterized by a concerted shift in drug susceptibility. The presence of an intact ATR, associated with growth in continuous culture at pH 5, leads to increased sensitivity to 22 compounds and decreased sensitivity to a separate set of 20 compounds. Disruption of the ATR in a mutant lacking the fabM gene resulted in a susceptibility profile that was distinct from the result of our results. This suggests that loss of unsaturated fatty acids produces a physiological change that is not only measurable, but perhaps more significant than the process of ATR. Additional tests revealed that S. mutans exhibits a distinct drug susceptibility profile compared to a closely related, non-cariogenic bacterium, S. gordonii. Overall, shifts in S. mutans susceptibility patterns based on pH of growth medium or type of culture (batch vs. continuous culture), indicate that the ATR can be tracked using changes in drug susceptibility profile. Furthermore, our results provide clues that compounds could be useful in treatment of dental caries as well as providing molecular tools to study shifts in physiology of disease-associated bacteria.