Abstract
The emergence of multidrug-resistant bacteria presents a severe threat to public health and causes extensive losses in livestock husbandry and aquaculture. Effective strategies to control such infections are in high demand. Enhancing host immunity is an ideal strategy with fewer side effects than antibiotics. To explore metabolite candidates, we applied a metabolomics approach to investigate the metabolic profiles of mice after Klebsiella pneumoniae infection. Compared with the mice that died from K. pneumoniae infection, mice that survived the infection displayed elevated levels of l-valine. Our analysis showed that l-valine increased macrophage phagocytosis, thereby reducing the load of pathogens; this effect was not only limited to K. pneumoniae but also included Escherichia coli clinical isolates in infected tissues. Two mechanisms are involved in this process: l-valine activating the PI3K/Akt1 pathway and promoting NO production through the inhibition of arginase activity. The NO precursor l-arginine is necessary for l-valine-stimulated macrophage phagocytosis. The valine-arginine combination therapy effectively killed K. pneumoniae and exerted similar effects in other Gram-negative (E. coli and Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus) bacteria. Our study extends the role of metabolism in innate immunity and develops the possibility of employing the metabolic modulator-mediated innate immunity as a therapy for bacterial infections.
Highlights
Multidrug-resistant bacterial pathogens, which are unresponsive to antibiotics, pose a substantial challenge to human health and animal husbandry
Intensive and inappropriate use of antibiotics dramatically leads to the development of drug resistance in bacterial pathogens, increasing the risk of severe diseases or death after exposure to multidrug-resistant bacteria [5, 39]
Our previous studies strongly suggested that the harnessing alanine and glucose, metabolites that are suppressed in antibiotic-resistant bacteria, could revert such a phenotype [24]
Summary
Multidrug-resistant bacterial pathogens, which are unresponsive to antibiotics, pose a substantial challenge to human health and animal husbandry. Gram-negative bacteria with extendedspectrum beta-lactamases (ESBLs), methicillin-resistant Staphylococcus aureus (MRSA), and Mycobacterium tuberculosis are the top three harmful pathogens around the world that can hardly be eliminated due to multidrug resistance [1, 2]. Among these Gram-negative bacteria with ESBLs, Klebsiella pneumoniae is a typical pathogen with high emergence that frequently promote empirical therapy failures [3, 4]. One possible approach would be to enhance the innate immune response of the infected host, which would restore the defense ability to kill the bacterial pathogen in a relatively risk-free manner [5].
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