Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.14 (ATP synthase)
 7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gentamicin is an aminoglycoside antibiotic widely used to treat many types of bacterial infections. Although its properties, his clinical use is limited due to the occurrence of nephrotoxicity, which has been related to mitochondrial dysfunction. Carvedilol, an antihypertensive drug with strong antioxidant properties, has been tested in order to prevent gentamicin nephrotoxicity. This study aimed to test this hypothesis using a rat model of gentamicin-induced nephrotoxicity. Animals were treated subcutaneously with DMSO (control) (0.4%/kg/24h bw) for 11days; with carvedilol (2mg/kg/24h bw) for 11days; with gentamicin (60mg/kg/24h bw) for the last 8days and with carvedilol (2mg/kg/24h bw) for 11days and with gentamicin (60mg/kg/24h bw) for the last 8days. Estimations of urine creatinine, urine carboxylic acids, blood urea, serum creatinine and glomerular filtration rate were carried out after the last administered dose of gentamicin. Mitochondria functionality was analyzed by monitoring its bioenergetics function and cardiolipin oxidized products were analyzed by ESI-MS. The kidneys were also examined for morphological changes. Gentamicin caused marked nephrotoxicity and mitochondrial dysfunction as evidenced by several mitochondrial parameters. Carvedilol did not induce significant changes while the co-treatment exacerbated the negative effect of gentamicin although maintaining ATP levels and membrane potential. Kidneys from gentamicin treated rats, with and without carvedilol, showed necrosis of tubular cells in renal cortex. Higher values on relative abundance of cardiolipin oxidation products identified as [M-2H]2- ions, at m/z 771 were observed in the groups treated with gentamicin. The observed effects were associated to a possible interaction of carvedilol with F1F0-ATP synthase that merit further investigation. In conclusion, carvedilol may contribute to the exacerbation of renal dysfunction induced by gentamicin, at least in some physiological and biochemical parameters. From a clinical perspective, and until further conclusions, cautious use of both drugs in combination is advised with particular emphasis in patients presenting mitochondrial disorders.
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PMID:Carvedilol exacerbate gentamicin-induced kidney mitochondrial alterations in adult rat. 2789 31

The emergence of antimicrobial resistance severely threatens our ability to treat bacterial infections. While acquired resistance has received considerable attention, relatively little is known of intrinsic resistance that allows bacteria to naturally withstand antimicrobials. Gene products that confer intrinsic resistance to antimicrobial agents may be explored for alternative antimicrobial therapies, by potentiating the efficacy of existing antimicrobials. In this study, we identified the intrinsic resistome to a broad spectrum of antimicrobials in the human pathogen, Staphylococcus aureus. We screened the Nebraska Transposon Mutant Library of 1920 single-gene inactivations in S. aureus strain JE2, for increased susceptibility to the anti-staphylococcal antimicrobials (ciprofloxacin, oxacillin, linezolid, fosfomycin, daptomycin, mupirocin, vancomycin, and gentamicin). Sixty-eight mutants were confirmed by E-test to display at least twofold increased susceptibility to one or more antimicrobial agents. The majority of the identified genes have not previously been associated with antimicrobial susceptibility in S. aureus. For example, inactivation of genes encoding for subunits of the ATP synthase, atpA, atpB, atpG and atpH, reduced the minimum inhibitory concentration (MIC) of gentamicin 16-fold. To elucidate the potential of the screen, we examined treatment efficacy in the Galleria mellonella infection model. Gentamicin efficacy was significantly improved, when treating larvae infected with the atpA mutant compared to wild type cells with gentamicin at a clinically relevant concentration. Our results demonstrate that many gene products contribute to the intrinsic antimicrobial resistance of S. aureus. Knowledge of these intrinsic resistance determinants provides alternative targets for compounds that may potentiate the efficacy of existing antimicrobial agents against this important pathogen.
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PMID:Genome-Wide Identification of Antimicrobial Intrinsic Resistance Determinants in Staphylococcus aureus. 2806 45