Particular Amino Acid on Lateral Interface Maintains FtsZ Function Under Acid Stress in Streptococcus mutans

FtsZ is the core protein for cell division in bacteria that can polymerize into Z-rings and drive cytokinesis. Understanding how bacteria maintain the correct function of FtsZ under various environmental stresses is crucial for novel antibacterial drug discovery. Our previous study revealed that the FtsZ in S. mutans has higher self-assembly and GTPase activity under acidic stress, which may be responsible for the cariogenesis of S. mutans. However, the mechanism is still unknown. Here, we further reported the crystal structure of S. mutans FtsZ, revealing a unique lateral interface. Through protein polymerization and GTPase ability assay, we experimentally demonstrated that mutation of Arg68 on this lateral interface significantly reduced the functional activity of FtsZ in an acidic environment. The phenotype assay and rat caries model further showed that mutation of Arg68 effectively inhibited the acid resistance of S. mutans and the occurrence and progress of dental caries in vivo. By employing a molecular dynamics simulation analysis, we conclude that mutation of Arg68 disrupts the conformation change necessary for SmFtsZ polymerization under acidic conditions. Our study proposes a novel mechanism to maintain FtsZ function in bacteria and could be a potential target for antimicrobial drugs to inhibit the growth of S. mutans in an acidic environment. Significance StatementFtsZ is the core protein that drives cytokinesis. Maintaining the self-assembly and GTPase activity of FtsZ plays a critical role in cell growth under environmental stress. Currently, research on FtsZ function maintenance under stress mainly focuses on model organisms, with less on other pathogenic bacteria. This study reveals a novel structural mechanism for the acidic tolerance of FtsZ in S. mutans which survives in strongly acidic surroundings. Meanwhile, Arg68 on the lateral interface of SmFtsZ may be a potential therapeutic target to regulate microecology and combat S. mutans-associated dental caries.