l-Serine potentiates fluoroquinolone activity against Escherichia coli by enhancing endogenous reactive oxygen species production.
The increase in multiple antimicrobial-resistant bacteria seriously threatens global public health. Novel effective strategies are urgently needed. l-Serine was reported as the most effective amino acid inhibitor against bacterial growth and can sensitize Escherichia coli cells to gentamicin. It is currently unknown whether l-serine affects other type of antibiotics such as β-lactams and fluoroquinolones.



Using E. coli, we studied the combination of l-serine with diverse antibiotics against laboratory and clinical E. coli cultures and persisters. The intracellular NAD(+)/NADH level and ROS were determined using kits. Total cellular iron was determined by using a colorimetric ferrozine-based assay.



Exogenous l-serine sensitized E. coli ATCC 25922 and clinically isolated fluoroquinolone-resistant E. coli to fluoroquinolones. This potentiation is independent of growth phase. Addition of serine increases the production of NADH. The underlying mechanism of this strategy is that the combination of serine with ofloxacin or moxifloxacin increases the NAD(+)/NADH ratio, disrupts the Fe-S clusters and increases the production of endogenous reactive oxygen species. Furthermore, we used a serine and ofloxacin or moxifloxacin combination in vitro to combat bacterial persister cells, compared with antibiotic treatment alone; combinational treatments of persister cells with antibiotics and l-serine resulted in a significantly greater decrease in cell viability.



To our knowledge, this is the first report that l-serine can potentiate the action of ofloxacin or moxifloxacin against Gram-negative bacteria and could constitute a new strategy for the eradication of bacterial infections.
Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environment Three Gorges Reservoir, Ministry of Education, School of Life Sciences, Southwest University, Chongqing 400715, China.
Xiangke
X
Duan
Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environment Three Gorges Reservoir, Ministry of Education, School of Life Sciences, Southwest University, Chongqing 400715, China.
Xue
X
Huang
Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environment Three Gorges Reservoir, Ministry of Education, School of Life Sciences, Southwest University, Chongqing 400715, China.
Xiaoyu
X
Wang
Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environment Three Gorges Reservoir, Ministry of Education, School of Life Sciences, Southwest University, Chongqing 400715, China.
Shuangquan
S
Yan
Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environment Three Gorges Reservoir, Ministry of Education, School of Life Sciences, Southwest University, Chongqing 400715, China Hanhong College, Southwest University, Chongqing 400715, China.
Siyao
S
Guo
Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environment Three Gorges Reservoir, Ministry of Education, School of Life Sciences, Southwest University, Chongqing 400715, China Department of Clinical Microbiology, College of Medical Laboratory Sciences, Omdurman Islamic University, Omdurman, Khartoum, Sudan.
Abualgasim Elgaili
AE
Abdalla
The Fifth People's Hospital of Chongqing, Chongqing 400715, China.
Changwu
C
Huang
Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-Environment Three Gorges Reservoir, Ministry of Education, School of Life Sciences, Southwest University, Chongqing 400715, China georgex@swu.edu.cn.
Jianping
J
Xie
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003600:Cytosol / Q000737:chemistry; D004347:Drug Interactions; D004926:Escherichia coli / Q000187:drug effects*; D024841:Fluoroquinolones / Q000494:pharmacology*; D007501:Iron / Q000032:analysis; D009243:NAD / Q000032:analysis; D017382:Reactive Oxygen Species / Q000032:analysis* / Q000633:toxicity; D012694:Serine / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D017382:Reactive Oxygen Species; D009243:NAD; D012694:Serine; D007501:Iron