Glycine, serine and threonine metabolism confounds efficacy of complement-mediated killing

Zhi-xue Cheng, Chang Guo, Zhuang-gui Chen, Tian-ci Yang, Jian-ying Zhang, Jie Wang, Jia-xin Zhu, Dan Li, Tian-tuo Zhang (), Hui Li (), Bo Peng () and Xuan-xian Peng ()
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Zhi-xue Cheng: Sun Yat-sen University, University City
Chang Guo: Sun Yat-sen University, University City
Zhuang-gui Chen: Third Affiliated Hospital of Sun Yat-sen University
Tian-ci Yang: Zhongshan Hospital of Xiamen University
Jian-ying Zhang: Zhengzhou University
Jie Wang: Sun Yat-sen University, University City
Jia-xin Zhu: Third Affiliated Hospital of Sun Yat-sen University
Dan Li: Sun Yat-sen University, University City
Tian-tuo Zhang: Third Affiliated Hospital of Sun Yat-sen University
Hui Li: Sun Yat-sen University, University City
Bo Peng: Sun Yat-sen University, University City
Xuan-xian Peng: Sun Yat-sen University, University City

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract Serum resistance is a poorly understood but common trait of some difficult-to-treat pathogenic strains of bacteria. Here, we report that glycine, serine and threonine catabolic pathway is down-regulated in serum-resistant Escherichia coli, whereas exogenous glycine reverts the serum resistance and effectively potentiates serum to eliminate clinically-relevant bacterial pathogens in vitro and in vivo. We find that exogenous glycine increases the formation of membrane attack complex on bacterial membrane through two previously unrecognized regulations: 1) glycine negatively and positively regulates metabolic flux to purine biosynthesis and Krebs cycle, respectively. 2) α-Ketoglutarate inhibits adenosine triphosphate synthase, which in together promote the formation of cAMP/CRP regulon to increase the expression of complement-binding proteins HtrE, NfrA, and YhcD. The results could lead to effective strategies for managing the infection with serum-resistant bacteria, an especially valuable approach for treating individuals with weak acquired immunity but a normal complement system.

Date: 2019
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DOI: 10.1038/s41467-019-11129-5

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