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.
Highlights
Serum resistance is a poorly understood but common trait of some difficult-to-treat pathogenic strains of bacteria
We showed there is a link between bacterial serum resistance with metabolism[29,30]
A web-based metabolomics pathway analysis tool, MetPA, was used to evaluate the potential impact of differential metabolite abundance on metabolic pathways in the bacterial strain. This analysis identified 8 pathways differentially-expressed in E. coli K12 in the presence of serum, with the largest predicted differential effect involving glycine, serine and threonine metabolism, with secondary and tertiary impact on alanine, aspartate and glutamate metabolism and the Krebs cycle (TCA cycle), respectively (Fig. 1c, d)
Summary
Serum resistance is a poorly understood but common trait of some difficult-to-treat pathogenic strains of bacteria. A significant number of both Gram-negative and Gram-positive bacteria survive and proliferate in human blood that has a fully functional complement system These pathogens are referred to as serum-resistant bacteria, and they are associated with potentially serious systemic infections[3,4,5]. Metabolism plays roles in serum susceptibility, e.g., ferric uptake regulator (Fur) confers serum resistance[21,22] and O2 consumption, adenine uptake, and glucose consumption increase are characteristic metabolic features when bacteria were exposed to serum[23,24] These findings provide a clue to the molecular basis of serum resistance in Gram-negative bacteria[6,7,8,9,10,18,19,20,21,22]. We describe a framework based on functional metabolomics and metabolite perturbation, that might lead to a novel approach for controlling and/or preventing acute infection with serumresistant and/or antibiotic-resistant pathogens
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