Abstract
Multidrug-resistant Pseudomonas aeruginosa has become one of global threat pathogens for human health due to insensitivity to antibiotics. Recently developed reprogramming metabolomics can identify biomarkers, and then, the biomarkers were used to revert the insensitivity and elevate antibiotic-mediated killing. Here, the methodology was used to study cefoperazone/sulbactam (SCF)-resistant P. aeruginosa (PA-RSCF) and identified reduced glycolysis and pyruvate cycle, a recent clarified cycle providing respiratory energy in bacteria, as the most key enriched pathways and the depressed glucose as one of the most crucial biomarkers. Further experiments showed that the depression of glucose was attributed to reduction of glucose transport. However, exogenous glucose reverted the reduction to elevate intracellular glucose via activating glucose transport. The elevated glucose fluxed to the glycolysis, pyruvate cycle, and electron transport chain to promote downstream proton motive force (PMF). Consistently, exogenous glucose did not promote SCF-mediated elimination but potentiated aminoglycosides-mediated killing since aminoglycosides uptake is PMF-dependent, where amikacin was the best one. The glucose-potentiated amikacin-mediated killing was effective to both lab-evolved PA-RSCF and clinical multidrug-resistant P. aeruginosa. These results reveal the depressed glucose uptake causes the reduced intracellular glucose and expand the application of metabolome-reprogramming on selecting conventional antibiotics to achieve the best killing efficacy.
Highlights
Pseudomonas aeruginosa is one of the most important opportunistic pathogens, whose clinical relevance is due to the high morbidity/mortality in subjects with compromised respiratory function, such as ventilator-associated pneumonia and cystic fibrosis
Glucose concentrations were increased in an exogenous glucose dose-dependent manner (Figure 5E). These results indicate that expression of genes encoding glucose transport is reduced in PA-R compared with P. aeruginosa (PA-S), which is related to minimum inhibitory concentration (MIC) and responsible for the depressed glucose concentration in PA-RSCF
This finding is supported by the event that the depressed glucose is linked to the reduced glycolysis, P cycle, and electron transport chain, while exogenous glucose activates these metabolic pathways of the central carbon metabolism in PA-RSCF
Summary
Pseudomonas aeruginosa is one of the most important opportunistic pathogens, whose clinical relevance is due to the high morbidity/mortality in subjects with compromised respiratory function, such as ventilator-associated pneumonia and cystic fibrosis. It can cause several acute and chronic infections, including infections of skin and soft tissues, meningitis, Glucose-Potentiated Amikacin Killing urinary tract, bone and joint, bacteremia corneal infections, abscess, conjunctival erythema, and a variety of systemic diseases associated with genetic diseases, in immunocompromised patients, such as those with diabetes mellitus and individuals receiving chemotherapy (Al-Wrafy et al, 2017). Despite the significant advances in therapeutic practices, eradication of P. aeruginosa has become increasingly difficult (Pang et al, 2019) This is because the bacterium produces an armoury of products which modify its infective niche to ensure bacterial survival (Cripps et al, 1995). Antibiotics are still the first line of drugs to treat the infection caused by the bacterium
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