Magnesium Links Starvation-Mediated Antibiotic Persistence to ATP
Tao Xu,
Xuyang Wang,
Lu Meng,
Mengqi Zhu,
Jing Wu,
Yuanyuan Xu,
Ying Zhang,
Wenhong Zhang
Affiliations
Tao Xu
Department of Infectious Diseases, National Clinical Research Center for Aging and Medicine, Huashan Hospital, State Key Laboratory of Genetic Engineering, School of Life Science, Key Laboratory of Medical Molecular Virology (MOE/MOH) and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
Xuyang Wang
Department of Infectious Diseases, National Clinical Research Center for Aging and Medicine, Huashan Hospital, State Key Laboratory of Genetic Engineering, School of Life Science, Key Laboratory of Medical Molecular Virology (MOE/MOH) and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
Lu Meng
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
Mengqi Zhu
Department of Infectious Diseases, National Clinical Research Center for Aging and Medicine, Huashan Hospital, State Key Laboratory of Genetic Engineering, School of Life Science, Key Laboratory of Medical Molecular Virology (MOE/MOH) and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
Jing Wu
Department of Infectious Diseases, National Clinical Research Center for Aging and Medicine, Huashan Hospital, State Key Laboratory of Genetic Engineering, School of Life Science, Key Laboratory of Medical Molecular Virology (MOE/MOH) and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
Yuanyuan Xu
Department of Infectious Diseases, National Clinical Research Center for Aging and Medicine, Huashan Hospital, State Key Laboratory of Genetic Engineering, School of Life Science, Key Laboratory of Medical Molecular Virology (MOE/MOH) and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
Ying Zhang
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
Wenhong Zhang
Department of Infectious Diseases, National Clinical Research Center for Aging and Medicine, Huashan Hospital, State Key Laboratory of Genetic Engineering, School of Life Science, Key Laboratory of Medical Molecular Virology (MOE/MOH) and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
ABSTRACT Bacterial persisters emerge and increase in numbers over time as a bacterial culture grows from log phase to stationary phase. However, the underlying basis of the inevitable tendency is unclear. In this study, we investigated the role of nutrients in starvation-mediated persister formation of Staphylococcus aureus. By screening of nutrient components, we found that starvation-induced persister formation of log-phase cultures could be reversed by addition of magnesium (Mg2+) but not amino acids, nucleotides, or other salts. Further, deprivation of extracellular Mg2+ reduced cytoplasmic ATP, inducing persistence without affecting cytoplasmic Mg2+ or membrane potential. Finally, we showed that Mg2+ reduced expression of stationary cell marker genes, cap5A and arcA. These findings indicate a connection between Mg2+ levels and ATP, which represents metabolic status and mediates antibiotic persistence during growth. IMPORTANCE Various genes have been identified to be involved in bacterial persister formation regardless of the presence or absence of persister genes. Despite recent discoveries of the roles of ATP and membrane potential in persister formation, the key element that triggers change of ATP or membrane potential remains elusive. Our work demonstrates that Mg2+ instead of other ions or nutrient components is the key element for persistence by inducing a decrease of cytoplasmic ATP, which subsequently induces persister formation. In addition, we observed tight regulation of genes for Mg2+ transport in different growth phases in S. aureus. These findings indicate that despite being a key nutrient, Mg2+ also served as a key signal in persister formation during growth.
