Inhibitor resistant class A beta-lactamases.
ABSTRACT Beta-lactamase inhibitors (clavulanic acid, tazobactam, and sulbactam) greatly enhance the therapeutic efficacy of their partner antibiotics (amoxacillin, ampicillin, piperacillin, and ticarcillin) against common enteric and non-enteric organisms possessing class A beta-lactamases. Unfortunately, the number of class A enzymes being discovered that are resistant to these combinations is increasingly rapidly. The TEM and SHV class A beta-lactamases resistant to inhibitors have point mutations in critical amino acids important for catalysis. Compared to the wild type beta-lactamase, inhibitor resistant enzymes are inefficient at hydrolyzing benzylpenicillin, aminopenicillins, and cephalosporins. Nevertheless, hyper-production of these enzymes resulting from mutations in the promoter region can confer substantial levels of resistance. Understanding the microbiologic and kinetic properties of these inhibitor resistant class A beta-lactamases can lead to the design of more potent beta-lactam compounds as well as more effective inhibitors.
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ABSTRACT: Acquired resistance to penicillin-beta-lactamase inhibitor combinations in Escherichia coli is due to: (i) penicillinase hyperproduction due to the presence of the bla(TEM-1) gene in small multicopy plasmids or strong promoters; (ii) overproduction of constitutive AmpC cephalosporinase; and (iii) OXA-type and inhibitor-resistant TEM (IRT) beta-lactamases. IRT enzymes emerge via mutational events from TEM-1 or TEM-2 beta-lactamases that affect substrate affinity for beta-lactamase inhibitors. They are mainly isolated in urinary infections from community patients. Prevalence is variable, depending on geographical area, detection methods and potential selection pressure. These enzymes may evolve into complex mutants (CMT enzymes), which also confer resistance to extended-spectrum cephalosporins. CTX-M enzymes with the IRT phenotype have not been detected to date. New studies of IRT enzymes, including population structure, association with virulence traits and plasmid dispersion, are needed.Clinical Microbiology and Infection 02/2008; 14 Suppl 1:53-62. · 4.54 Impact Factor
Article: Beta-lactamases in ampicillin-resistant Escherichia coli isolates from foods, humans, and healthy animals.[show abstract] [hide abstract]
ABSTRACT: TEM-, SHV-, and OXA-type beta-lactamases were studied by PCR with 124 ampicillin-resistant (AMP(r)) Escherichia coli isolates recovered from foods of animal origin (n = 20) and feces of humans (n = 49) and healthy animals (n = 55). PCR showed that 103 isolates were positive for TEM and negative for SHV and OXA. Three E. coli isolates showed a positive reaction for OXA, and one showed a positive reaction for SHV. The remaining 17 E. coli isolates were negative for the three enzymes by PCR. Fifty-seven of the 103 bla(TEM) amplicons were sequenced. Different molecular variants of bla(TEM-1) were found in 52 isolates: bla(TEM-1a) (n = 9), bla(TEM-1b) (n = 36), bla(TEM-1c) (n = 6), and bla(TEM-1f) (n = 1). Four inhibitor-resistant TEM (IRT) beta-lactamase-encoding genes were also detected: bla(TEM-30c) (IRT-2), bla(TEM-34b) (IRT-6), bla(TEM-40b) (IRT-11), and bla(TEM-51a) (IRT-15). A new bla(TEM) gene, named bla(TEM-95b), which showed a mutation in amino acid 145 (P-->A) was detected. It was found in a food isolate of chicken origin (AMP(r), amoxicillin-clavulanic acid susceptible). The promoter region in 24 bla(TEM) amplicons was analyzed, and the weak P3 promoter was found in 23 of them (bla(TEM-1) in 20 amplicons and bla(TEM-51a), bla(TEM-30c), and bla(TEM-95b) in 1 amplicon each). The strong Pa/Pb promoter was found only in the bla(TEM-34b) gene. No extended-spectrum beta-lactamases were detected. Mutations at position -42 or -32 in the ampC gene promoter were demonstrated in 4 of 10 E. coli isolates for which the cefoxitin MIC was >/=16 micro g/ml. Different variants of bla(TEM-1) and IRT bla(TEM) genes were found among the AMP(r) E. coli isolates from foods and the feces of humans and healthy animals, and a new gene, bla(TEM-95b) (P3), was detected.Antimicrobial Agents and Chemotherapy 10/2002; 46(10):3156-63. · 4.84 Impact Factor