Methicillin-resistant Staphylococcus aureus (S. aureus) (MRSA) represents more and more S. aureus infections. MecA, the novel coding gene of penicillin-binding protein (PBP) 2a of MRSA, is the key resistance factor of β-lactam, but little is known about the evolution of this gene. Given the crucial role of mecA in S. aureus physiology and β-lactam resistance, the selective forces may contribute to adaptation of the bacteria to the special environments such as its host or antibiotics. To understand the evolution of this gene, we screened GenBank database and analyzed mecA of 249 S. aureus strains. Twenty-nine unique alleles with 26 unique amino acid sequences were identified. Phylogenetic analysis showed three main groups of mecA in the global S. aureus strains. Analysis of these alleles using codon-substitution models (M8, M3, and M2a) and likelihood ratio tests (LRTs) of the codeML package and a random-effects likelihood (REL) method of HyPhy package for the site-specific ratio of nonsynonymous to synonymous substitution rates suggested that fourteen sites in the allosteric domain of PBP2a have been subjected to strong positive selection pressure. Mutations of two positive selection sites (N146K and E239K) were reported to be essential for ceftaroline- or L-695, 256-resistant. Further study indicated that the positive selection pressure might be more likely related to the host's inflammatory or immune response during S. aureus infection. Our studies provide the first evidence of positive Darwinian selection in the mecA of S. aureus, contributing to a better understanding of the adaptive mechanism of this bacterium.

01 Feb 2004·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

PBP 2a Mutations Producing Very-High-Level Resistance to Beta-Lactams

Q2 · MEDICINE

Article

Author: Zhang, Hong-Zhong ; Katayama, Yuki ; Chambers, Henry F.

ABSTRACT Resistance to the beta-lactam class of antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) is mediated by PBP 2a, a synthetic bacterial cell wall penicillin-binding protein with a low affinity of binding to beta-lactams that is encoded by mecA . Beta-lactams that bind to PBP 2a with a high affinity and that are highly active against MRSA are under development. The potential for the emergence of resistance to such compounds was investigated by passage of homogeneous MRSA strain COL in L-695,256, an investigational carbapenem. A highly resistant mutant, COL52, expressed PBP 2a in which a two-amino-acid deletion mutation and three single-amino-acid substitution mutations were present. To examine the effects of these mutations on the resistance phenotype and PBP 2a production, plasmids carrying (i) PBP 2a with two or three of the four mutations, (ii) wild-type PBP 2a, or (iii) COL52 PBP 2a were introduced into methicillin-susceptible COL variants COLnex and COL52ex, from which the staphylococcus cassette chromosome mec (SCC mec ) has been excised, as indicated by the “ex” suffix. Two amino acids substitutions, E→K 237 within the non-penicillin-binding domain and V→E 470 near the SDN 464 conserved penicillin-binding motif in the penicillin-binding domain in COL52, were important for high-level resistance. The highest level of resistance was observed when all four mutations were present. The emergence of PBP 2a-mediated resistance to beta-lactams that bind to PBP 2a with a high affinity is likely to require multiple mutations in mecA ; chromosomal mutations appear to have a minor role.

01 Apr 1996·ToxicologyQ3 · MEDICINE

Species specificity of 2-aryl carbapenem-induced immunemediated hemolytic anemia in primates

Q3 · MEDICINE

Article

Author: George R. Lankas ; Yves Bailly ; John B. Coleman ; Hilton J. Klein

L-695,256 is a novel 2-fluorenonyl carbapenem antibiotic with significant antimicrobial activity against strains of methicillin-resistant Staphylococci. This prototype compound was administered intravenously to rhesus monkeys (Macaca mulatta) at does of 50 or 200 mg/kg/day for 2 weeks to assess toxicity and found to induce a hemolytic anemia characterized by extravascular hemolysis and splenomegaly. A subsequent study in this species in which 100 mg/kg/day was administered i.v. for 4 weeks showed that all animals were direct antiglobulin test (Coombs' test) positive for IgG with 20-25% reductions in the erythron. Following 3 weeks of recovery, the erythron had returned to normal, although it took an additional 2 months for the Coombs' test to become negative. Challenge of these same animals with 0.5 million U/kg (300 mg/kg/day) of penicillin intravenously indicated no apparent cross-reactivity. Since attempts to establish a model for this immune-mediated hemolytic anemia with this drug in rats or mice were unsuccessful, a 2-week i.v. study in squirrel monkeys (Saimiri sciureus) was conducted at a dose of 200 mg/kg/day. All animals in this study remained Coombs' test negative with no changes in the erythron, suggesting an increased sensitivity to beta-lactam-induced anemia in rhesus monkeys compared to other species. Further support for this hypothesis was obtained using the cephalosporin antibiotic, cefotetan. This compound induced a high incidence of Coombs' test positive hemolytic anemia at clinically relevant doses in rhesus monkeys, despite a very low incidence of this adverse effect in patients with many years of clinical use. These data suggest that although rhesus monkeys respond in a qualitatively similar manner to humans with regard to high doses of beta-lactam antibiotics, their sensitivity may overestimate the risk of immune-mediated hemolytic anemia for clinical use.

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Indication	Highest Phase	Country/Location	Organization	Date
Staphylococcal Infections	Discovery	United States	Merck & Co., Inc.	-

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