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  • Title: Inhibition of OXA-1 beta-lactamase by penems.
    Author: Bethel CR, Distler AM, Ruszczycky MW, Carey MP, Carey PR, Hujer AM, Taracila M, Helfand MS, Thomson JM, Kalp M, Anderson VE, Leonard DA, Hujer KM, Abe T, Venkatesan AM, Mansour TS, Bonomo RA.
    Journal: Antimicrob Agents Chemother; 2008 Sep; 52(9):3135-43. PubMed ID: 18559643.
    Abstract:
    The partnering of a beta-lactam with a beta-lactamase inhibitor is a highly effective strategy that can be used to combat bacterial resistance to beta-lactam antibiotics mediated by serine beta-lactamases (EC 3.2.5.6). To this end, we tested two novel penem inhibitors against OXA-1, a class D beta-lactamase that is resistant to inactivation by tazobactam. The K(i) of each penem inhibitor for OXA-1 was in the nM range (K(i) of penem 1, 45 +/- 8 nM; K(i) of penem 2, 12 +/- 2 nM). The first-order rate constant for enzyme and inhibitor complex inactivation of penems 1 and 2 for OXA-1 beta-lactamase were 0.13 +/- 0.01 s(-1) and 0.11 +/- 0.01 s(-1), respectively. By using an inhibitor-to-enzyme ratio of 1:1, 100% inactivation was achieved in <or=900 s and the recovery of OXA-1 beta-lactamase activity was not detected at 24 h. Covalent adducts of penems 1 and 2 (changes in molecular masses, +306 +/- 3 and +321 +/- 3 Da, respectively) were identified by electrospray ionization mass spectrometry (ESI-MS). After tryptic digestion of OXA-1 inactivated by penems 1 and 2, ESI-MS and matrix-assisted laser desorption ionization-time-of-flight MS identified the adducts of 306 +/- 3 and 321 +/- 3 Da attached to the peptide containing the active-site Ser67. The base hydrolysis of penem 2, monitored by serial (1)H nuclear magnetic resonance analysis, suggested that penem 2 formed a linear imine species that underwent 7-endo-trig cyclization to ultimately form a cyclic enamine, the 1,4-thiazepine derivative. Susceptibility testing demonstrated that the penem inhibitors at 4 mg/liter effectively restored susceptibility to piperacillin. Penem beta-lactamase inhibitors which demonstrate high affinities and which form long-lived acyl intermediates may prove to be extremely useful against the broad range of inhibitor-resistant serine beta-lactamases present in gram-negative bacteria.
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