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Interaction of clavulanate with the beta-lactamases of Streptomyces albus G and Actinomadura R39.

ABSTRACT: The reactions of beta-lactamases of Actinomadura R39 and Streptomyces albus G with clavulanate proceed along branched pathways. Both enzymes perform the hydrolysis of this beta-lactam with rather high efficiencies (kcat. = 18s-1 and 52s-1 respectively). If large clavulanate/enzyme ratios are used, complete inactivation of the enzymes is observed. At lower ratios, inactivation is only partial. Irreversible inactivation occurs after 400 and 20000 turnovers for the A. R39 and S. albus G enzymes respectively. With the A. R39 beta-lactamase, a transiently inhibited complex is also formed that remains undetectable with the S. albus G beta-lactamase. Kinetic models are presented and studied for the interaction between clavulanate and both enzymes. A tentative general reaction scheme is also discussed.

SUBMITTER: Frere JM

PROVIDER: S-EPMC1153882 | biostudies-other | 1982 Dec

REPOSITORIES: biostudies-other

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Project description:This study analyzed the enzymatic basis and molecular epidemiology of amoxicillin-clavulanate-resistant Escherichia coli isolated by the microbiology laboratory of a United States tertiary care hospital. From October 1998 to December 1999, all E. coli isolates were screened for ampicillin-sulbactam resistance. Of 283 isolates that tested resistant to ampicillin-sulbactam, 69 unique patient isolates were also resistant to amoxicillin-clavulanate by disk diffusion testing (zone diameter </= 13 mm). These amoxicillin-clavulanate-resistant E. coli isolates underwent agar dilution testing, pulsed-field gel electrophoresis, PCR analysis, and isoelectric focusing. The mean age of study patients was 52 years; 78% were female. Among the isolates, 12 were nosocomial (rate of amoxicillin-clavulanate resistance = 4.7%) and 57 were community acquired (rate of amoxicillin-clavulanate resistance = 2.8%). No predominant strain was identified. By agar dilution testing, 67 isolates were nonsusceptible (39 resistant and 28 intermediate) to amoxicillin-clavulanate and 37 were piperacillin-tazobactam resistant but only 8 were ceftazidime resistant (ceftazidime MIC >/= 32 micro g/ml). Two isolates were susceptible to amoxicillin-clavulanic acid by agar dilution, although they were resistant by disk diffusion testing. The distribution of beta-lactamases was as follows: the TEM type alone was found in 52 isolates, the AmpC type was found in 4 isolates (2 identified as containing CMY-2), the TEM type and CMY-2 were found in 2 isolates, and the OXA type was found in 1 isolate. Also, there was one isolate with the TEM type and the SHV type and one with the TEM type and a second, unidentified enzyme. Among the isolates with TEM-type enzymes, two extended-spectrum beta-lactamase-producing isolates were identified but two isolates with inhibitor-resistant TEM (IRT) enzymes (one with TEM-34 [IRT-6] and the other with a novel enzyme [tentatively assigned the designation TEM-122]) were more interesting.

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Interaction of clavulanate with the beta-lactamases of Streptomyces albus G and Actinomadura R39.

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