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Streptococcus mutans, a biofilm-forming Gram-positive bacterium that resides in the human oral cavity, is considered to be the primary aetiological agent of human dental caries. A cell-envelope stress-sensing histidine kinase, LiaS, is considered to be important for expression of virulence factors such as glucan-binding protein C and mutacin production. In this study, a liaS mutant was subjected to phenotypic microarray (PM) analysis of about 2000 phenotypes, including utilization of various carbon, nitrogen, phosphate and sulfur sources; osmolytes; metabolic inhibitors; and susceptibility to toxic compounds, including several types of antibiotics. Compared to the parental strain UA159, the liaS mutant strain (IBS148) was more tolerant to various inhibitors that target protein synthesis, DNA synthesis and cell-wall biosynthesis. Some of the key findings of the PM analysis were confirmed in independent growth studies and by using antibiotic discs and E-test strips for susceptibility testing