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Modification of outer membrane proteins (OMPs) is the first line of Gram-negative bacteria defence against antimicrobials. Here we point to Proteus mirabilis OMPs and their role in antibiotic and phage resistance. Protein profiles of amikacin (AMKrsv), phage (Brsv) and amikacin/phage (AMK/Brsv) resistant variants of P. mirabilis were compared to that obtained for a wild strain. In resistant variants there were identified 14, 1, 5 overexpressed and 13, 5, 1 downregulated proteins for AMKrsv, Brsv and AMK/Brsv, respectively. Application of phages with amikacin led to reducing the number of up- and downregulated proteins compared to single antibiotic treatment. Proteins isolated in AMKrsv are involved in protein biosynthesis, transcription and signal transduction, which correspond to well-known mechanisms of bacteria resistance to aminoglycosides. In isolated OMPs several cytoplasmic proteins, important in antibiotic resistance, were identified, probably as a result of environmental stress, e.g. elongation factor Tu, asparaginyl-tRNA and aspartyl-tRNA synthetases. In Brsv there were identified: NusA and dynamin superfamily protein which could play a role in bacteriophage resistance. In the resistant variants proteins associated with resistance mechanisms occurring in biofilm, e.g. polyphosphate kinase, flagella basal body rod protein were detected. These results indicate proteins important in the development of P. mirabilis antibiofilm therapies.

Background: blaNDM-1-producing Acinetobacter baumannii (BP-AB) remains a critical problem in nosocomial infections, because of its resistance mediated by the biofilm formation and virulence factors. No studies have confirmed myrtenol's efficacy in inhibiting the biofilm formation and virulence associated with biofilm of BP-AB. Methods: The tested concentrations of myrtenol were wild type (A), 50 μg/mL (B), 100 μg/mL (C), 200 μg/mL (D), 250 μg/mL (E), and 300 μg/mL (F). Results: The BP-AB biofilm inhibition was significantly higher in the D, E, and F groups than in the A, B, and C groups. Myrtenol significantly reduced the air-liquid interface ring formation in glass tubes. It also effectively inhibited the attachment of BP-AB strains on polystyrene surfaces as shown by crystal violet staining. Microscopy showed a significant reduction in biofilm formation with dispersed BP-AB strains. The confocal laser scanning microscopy analysis showed a significant reduction in the biofilm's biomass, covered surface area, and thickness. The scanning electron microscopy analysis revealed significantly fewer BP-AB aggregates on the coverslip surface. In the CompStat analysis, the biofilm's biomass, maximum thickness, and surface-to-volume ratio were significantly reduced. The qPCR analysis revealed a significant down-regulation of bfmR, bap, csuA/B, and ompA expression, which positively correlated with the biofilm's biomass, maximum thickness, and surface-to-volume ratio in BP-AB strains. Myrtenol significantly improved the susceptibility of BP-AB to the antibiotics amikacin, piperacillin/tazobactam, cefoperazone/sulbactam, and ceftazidime. Conclusion: Myrtenol attenuates the BP-AB biofilm formation and virulence by suppressing the expression of bfmR, bap, csuA/B, and ompA. [ABSTRACT FROM AUTHOR]

Background: Carbapenem-resistant Enterobacteriaceae (CRE) meningitis are associated with poor outcomes and high mortality. Here, we report the first successful treatment case of serious meningitis caused by extremely carbapenem-resistant Enterobacter cloacae (minimum inhibitory concentration (MIC) of imipenem ≥16mg/L) with high-dose prolonged infusion of meropenem and i.v. amikacin plus intraventricular (IVT) amikacin. Case presentation: A 17-year-old girl developed meningitis from an extremely carbapenem-resistant Enterobacter cloacae (MIC of imipenem ≥16mg/L) as a complication of the removal of a giant central neurocytoma located in bilateral and third ventricles. The patient received four surgeries (one tumor excision and three external ventricular drainages) and was treated with a 70 days course of antibiotics therapy during 100 days hospitalization. Finally, she was safely and successfully treated with the high-dose prolonged infusion of meropenem and i.v. amikacin plus IVT amikacin. Conclusion: This case report shows the possibility of the antibiotic regimen of high-dose prolonged infusion of meropenem and i.v. amikacin plus IVT amikacin in the successful treatment of CRE meningitis (MIC of imipenem ≥16mg/L) especially when other antibiotics are unavailable or restricted. [ABSTRACT FROM AUTHOR]

[Display omitted] • The 7−OH MTX was the main culprit for MTX nephrotoxicity. • PERK/CHOP mediated ER stress was screened as key pathway by RNA-seq analysis. • Nobiletin could ameliorate the nephrotoxicity of 7−OH MTX through PERK/CHOP pathway. • Nobiletin could maintain Ca2+ homeostasis and reduce the production of ROS. Drug-induced nephrotoxicity is a frequent adverse event that contributes to acute kidney injury with tubular and/or glomerular lesions. Methotrexate (MTX) is a folate analog used against a myriad of malignancies and autoimmune diseases. Unfortunately, ambiguous renal toxicology limits its safe clinical usage. Based on our previous studies, 7−OH MTX as an overlooked oxidative metabolite of MTX was proposed to be the main culprit responsible for nephrotoxicity, while nobiletin, a naturally occurring polymethoxylated flavonoid screened from our prepared total phenolic extracts of Citrus aurantium L. (TPE-CA), was employed as a therapeutic agent for drug-drug interactions. According to the present study, nobiletin can ameliorate the renal accumulation of 7−OH MTX through the interaction with aldehyde oxidase. RNA-seq analysis revealed that 7−OH MTX was mainly related to protein processing in endoplasmic reticulum (ER) stress, with the PERK/CHOP pathway selected as the most significant for metabolic nephrotoxicity. Meanwhile, the cross-linked proteins and conducted signals were investigated by western blotting and further verified by GSK inhibition analyses. These results indicated that nobiletin protected renal function from MTX-induced nephrotoxicity by modulating metabolism and ameliorated the metabolic toxicity of 7−OH MTX on ER stress-induced PERK/CHOP conduction by maintaining Ca2+ homeostasis and reducing the production of reactive oxygen species. [ABSTRACT FROM AUTHOR]