Metabolic shift and antibiotic resistance have been reported in Pseudomonas aeruginosa. However, the global metabolic characteristics remain largely unknown. The present study characterizes the central carbon metabolism and its effect on other metabolic pathways in cefoperazone-sulbactam (SCF)-resistant P. aeruginosa (PA-RSCF). GC-MS-based metabolomics shows a repressed central carbon metabolism in PA-RSCF, which is confirmed by measuring expression of genes and activity of enzymes in the metabolism. Furthermore, expression of the genes that encode the enzymes for the first step of fatty acid biosynthesis, glutamate metabolism, and electron transport chain is reduced, confirmed by their enzymatic activity assay, and the key enzyme for riboflavin metabolism is also reduced, indicating the decreased metabolic flux to the four related metabolic pathways. Moreover, the role of the reduced riboflavin metabolism, being related to ROS generation, in SCF resistance is explored. Exogenous H2O2 potentiates SCF-mediated killing in a dose-dependent manner, suggesting that the decreased ROS resulted from the reduced riboflavin metabolism that contributed to the resistance. These results indicate that the repressed central carbon metabolism and related riboflavin metabolism contribute to SCF resistance, but increasing ROS can restore SCF sensitivity. These findings characterize the repressed central carbon metabolism and its effect on other metabolic pathways as the global metabolic features in PA-RSCF.

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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.

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Background: Extensive knowledge of allergic multimorbidities is required to improve the management of allergic diseases with the industrialization of China. However, the demography and allergen distribution patterns of allergic multimorbidities in China remain unclear, despite the increasing prevalence of allergies. Methods: This was a real-world, cross-sectional study of 1273 outpatients diagnosed with one or more allergic diseases in Guangzhou, the most populated city of southern China, with leading industrial and commercial centers, between April 2021 and March 2022. Seven allergic diseases (allergic rhinitis (AR), asthma (AS)/cough variant asthma (CVA), atopic dermatitis (AD)/eczema, food allergy (FA), allergic conjunctivitis (AC), drug allergy (DA), and anaphylaxis) were assessed. Positive rates of sensitization to different allergens were measured using an allergen detection system of the UniCAP (Pharmacia Diagnostics, Sweden) instrument platform to compare the groups of allergic multimorbidities against a single entity. Results: There were 659 (51.8%) males and 614 (48.2%) females aged from 4 months to 74 years included in the analysis. The study participants who were diagnosed with allergic diseases had an average of 1.6 diagnoses. Overall, 46.5% (592 of 1273) of the patients had more than one allergic condition, and allergic rhinitis was the most common type of multimorbidity. Women were more likely to suffer from an allergic disease alone, whereas allergic multimorbidities were more likely to be diagnosed in men (p = 0.005). In addition, allergic multimorbidities were common in all age groups, with an incidence ranging from 37.1% to 57.4%, in which children and adolescents were more frequently diagnosed with allergic multimorbidities than adults (18–60 years old) (all p < 0.05). Allergic multimorbidity was observed throughout the year. A difference in the positive rate of allergens sensitization and total immunoglobulin E (tIgE) levels between different allergic multimorbidities was observed. Conclusions: Allergic multimorbidities were very commonly found in nearly half of all patients with allergies. The proportion of allergic multimorbidities varied with the type of disease, sex, age, and allergen distribution pattern. These findings may help clinicians to develop “One health” strategies for the clinical management of allergic diseases.