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ABSTRACT Metabolic state-reprogramming approach was extended from Gram-negative bacteria to Gram-positive bacterium methicillin-resistant Staphylococcus aureus (MRSA) for identifying desired reprogramming metabolites to synergize existing antibiotic killing to MRSA. Metabolomics comparison between MRSA and methicillin-sensitive Staphylococcus aureus showed a depressed metabolic state in MRSA. Valine was identified as the most depressed metabolite/biomarker, and valine, leucine and isoleucine biosynthesis as the most enriched metabolic pathway. Thus, valine was used as a reprogramming metabolite to potentiate existing antibiotic killing to MRSA. Among the tested antibiotics, valine synergized cefoperazone-sulbactam (SCF) to produce the greatest killing effect. The combined effect of SCF and valine was demonstrated in clinical MRSA isolates and in mouse systemic and thigh infection models. Underlying mechanisms were attributed to valine-induced the activation of the pyruvate cycle/the TCA cycle and fatty acid biosynthesis. The activated pyruvate cycle/the TCA cycle elevated proton motive force by NADH and the activated fatty acid biosynthesis promoted membrane permeability by lauric acid. Both together increased cefoperazone uptake, which outpaces efflux action and thereby intracellular drug is elevated to effectively kill MRSA. These results provide the combination of valine and SCF to produce a new drug candidate effective against MRSA.IMPORTANCEMethicillin-resistant Staphylococcus aureus (MRSA) is possibly the most infamous example of antibiotic resistance and new antibiotics are urgently needed to control it. The present study used metabolic state-reprogramming approach to identify an ideal biomarker as an antibiotic adjuvant for reversing the metabolic state of MRSA. The most repressed valine was identified as the adjuvant. Exogenous valine most effectively potentiated cefoperazone-sulbactam (SCF) to kill MRSA in vitro and in vivo. Viability of 18 clinical MRSA isolates was reduced by the top 276.64-fold in the presence of valine and SCF. In mouse models, lower bacterial load in liver, spleen, kidney, thigh, and higher survival were determined in the SCF + valine than valine or SCF alone. Valine promoted MRSA to increase SCF uptake that overcomes the efflux and enzymatic hydrolysis. It also extended the PAE of SCF. These occur because valine activates the pyruvate cycle to elevate proton motive force by NADH and increases membrane permeability by lauric acid. Therefore, the combination of valine and SCF is a new drug candidate effective against MRSA.

OBJECTIVE: To systematically review the efficacy and safety of cefoperazone and sulbactam in the treatment of lower respiratory infection. METHODS: Randomized controlled trials on cefoperazone and sulbactam in the treatment of lower respiratory infection (the intervention group was given cefoperazone and sulbactam, no limits for dosage and courses; the control group was given other antibiotics, such as piperacillin tazobactam, ceftazidime, levofloxacin and moxifloxacin, also no limits for dosage and courses) were retrieved from the Cochrane Library, PubMed, Embase, CNKI and Wanfang Data, and the search date was up to Jun. 2021. After literature screening and data extracting, the literature quality was evaluated using the assessment tool of risk bias recommended in the Cochrane Systematic Assessor' s Handbook 5.1, and Meta-analysis was performed using RevMan 5. 3 software. RESULTS : Totally 16 studies were finally enrolled, including 1347 patients. Results of Meta-analysis indicated that the difference in clinical effective rate between intervention group and control group had no statistical significance ( OR = 1.18, 95%CI= 0. 87-1. 61,P>O. 05); in the subgroup analysis with piperacillin tazobactam as a control, the difference in clinical efficiency between intervention group and control group still had no statistical significance ( OR = 0. 80, 95%CI=O. 39-1. 65,P>O. 05 ) . The difference in bacterial clearance rate between intervention group and control group had no statistical significance (OR= l.13, 95% CI= 0. 76-1. 68, P> 0. 05) ; in the subgroup analysis with piperacillin tazobactam as control, the difference in bacterial clearance rate between intervention group and control group still had no statistical significance (OR= 0. 76, 95% CI= 0. 31-1. 91, P> 0. 05) ; There was no statistically significant difference in the incidence of adverse drug reactions between intervention group and control group ( OR= 0. 97, 95% CI= 0. 58- 1. 62,P>O. 05). CONCLUSIONS: The cefoperazone and sulbactam has similar clinical efficacy and safety with control drugs in the treatment of lower respiratory infection. [ABSTRACT FROM AUTHOR]