Journal
INFECTION AND DRUG RESISTANCE
Volume 13, Issue -, Pages 2593-2599Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/IDR.S263225
Keywords
amino acids; bacterial persisters; bactericidal antibiotics; cysteine; gram-negative bacteria
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Funding
- National Key Research and Development Program of China [2018YFA0903400]
- National Natural Science Foundation of China [31872526]
- Natural Science Foundation of Jiangsu Province of China [BK20190893]
- China Postdoctoral Science Foundation [2019M651984]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- Lift Engineering of Young Talents of Jiangsu Association for Science and Technology
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Purpose: Bacterial metabolism regulators offer a novel productive strategy in the eradication of antibiotic refractory bacteria, particularly bacterial persisters. However, the potential of amino acids in the fight against Gram-negative bacterial persisters has not been fully explored. The aim of this study is to investigate the potentiation of amino acids to antibiotics in combating Gram-negative bacterial persisters and to reveal the underlying mechanisms of action. Methods: Bactericidal activity of antibiotics in the absence or presence of amino acids was evaluated through detecting the reduction of bacterial CFUs. The ratio of NAD(+)/NADH in E. coli B2 persisters was determined using assay kit with WST-8. Bacterial respiration and ROS production were measured by the reduction of iodonitrotetrazolium chloride and fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate, respectively. Results: In this study, we found that cysteine possesses excellent synergistic bactericidal activity with ciprofloxacin against multiple Gram-negative bacterial persisters. Furthermore, the potentiation of cysteine was evaluated in exponential and stationary-phase E. coli ATCC 25922 and E. coli B2. Interestingly, cysteine significantly improves three bactericidal antibiotics killing against stationary-phase bacteria, but not exponential-phase bacteria, implying that the effect of cysteine correlates with the metabolic state of bacteria. Mechanistic studies revealed that cysteine accelerates the bacterial TCA cycle and promotes bacterial respiration and ROS production. These metabolic regulation effects of cysteine re-sensitive bacterial persisters to antibiotic killing. Conclusion: Collectively, our study highlights the synergistic bactericidal activity of bacterial metabolism regulators such as cysteine with commonly used antibiotics against Gram-negative bacterial persisters.
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