Targeting Mannitol Metabolism as an Alternative Antimicrobial Strategy Based on the Structure-Function Study of Mannitol-1-Phosphate Dehydrogenase in Staphylococcus aureus

Due to the shortage of effective antibiotics against drug-resistant Staphylococcus aureus , new targets are urgently required to develop next-generation antibiotics. We investigated mannitol-1-phosphate dehydrogenase of S. aureus USA300 ( Sa M1PDH), a key enzyme regulating intracellular mannitol levels, and explored the possibility of using Sa M1PDH as a target for developing antibiotic. Since mannitol is necessary for maintaining the cellular redox and osmotic potential, the homeostatic imbalance caused by treatment with a Sa M1PDH inhibitor or knockout of the gene encoding Sa M1PDH results in bacterial cell death through oxidative and/or mannitol-dependent cytolysis. We elucidated the molecular mechanism of Sa M1PDH and the structural basis of substrate and inhibitor recognition by enzymatic and structural analyses of Sa M1PDH. Our results strongly support the concept that targeting of Sa M1PDH represents an alternative strategy for developing a new class of antibiotics that cause bacterial cell death not by blocking key cellular machinery but by inducing cytolysis and reducing stress tolerance through inhibition of the mannitol pathway.