Penicillin-binding protein (PBP) 5 of Streptococcusfaecium has been shown to have a very low affinity for penicillin, and this PBP was suggested to be responsible for both the natural low susceptibility and high resistance to the antibiotic in this species (R. Fontana, R. Cerini, P. Longoni, A. Grossato, and P. Canepari, J. Bacteriol. 155:1343Bacteriol. 155: -1350Bacteriol. 155: , 1983. In this study, an S. faecium mutant (Revl4) hypersusceptible to penicillin was derived from the highly resistant S. faecium R40 treated with novobiocin, and its properties were compared with those of the parent and S. faecium PS, a relatively susceptible strain from which R40 was isolated. The hypersusceptible strain did not synthesize PBP 5, but it did resemble the parent in cell morphology, growth rate, and autolytic activity. In addition, it was highly susceptible to other beta-lactams but remained as susceptible as R40 and PS to antibiotics of a different mechanism of action. The affinity of individual PBPs for the beta-lactams tested was the same in all the strains. This finding suggested that Revl4 hypersusceptibility was due to the lack of PBP 5 and strongly supported the role of this protein in the mechanism of both natural low susceptibility and high-level resistance to beta-lactams in S. faecium.The synthesis of penicillin-binding proteins (PBPs) that show a very low affinity for beta-lactams (low-affinity PBPs) appears to be a newly recognized mechanism of intrinsic resistance to these antibiotics found in several gram-positive species (1, 9, 11).Described for the first time in a methicillin-resistant Staphylococcus aureus strain by Brown and Reynolds (1), lowaffinity PBPs are also produced by Streptococcus faecium and other species belonging to the enterococcus group (6, 9). S. faecium strains overproducing this protein (PBP 5) show very high penicillin MICs, can grow in the presence of a penicillin concentration saturating all PBPs but the lowaffinity PBP, and stop growing in the presence of the minimal concentration of antibiotic saturating this protein (9). These findings have led to the conclusion that low-affinity PBPs may be responsible for the characteristic low susceptibility of enterococci to beta-lactams and, when overproduced, for the capability of these microorganisms to become highly resistant to these antibiotics, a property not shared with other streptococci (9, 12). If this suggestion is correct, S. faecium strains unable to synthesize the low-affinity PBP should demonstrate a susceptibility for beta-lactams similar to that of other streptococci.In this report we describe a mutant of S. faecuium hypersusceptible to penicillin and lacking PBP 5. The comparison of the properties of this mutant with those of strains producing a different amount of PBP S provides fuirther strong evidence of the role of the low-affinity PBP in the mechanism of resistance to beta-lactams in this species.(This work was presented, in part, at the FEMS Symposium: Bacterial morphogenesis, Marseilles, France, 5 to 7 September 198...
Penicillin-binding protein (PBP) 5 of Streptococcus faecium ATCC 9790 has an unusually low affinity for penicillin (50%o binding occurred at a penicillin level of 8 ,ug/ml after 60 min of incubation, and the protein only became labeled after 20 min of incubation with high concentrations of radioactive penicillin). PBPs with similar properties are carried by strains of Streptococcus durans, Streptococcus faecalis, and Streptococcus lactis but not by strains of groups A, B, C, and G streptococci or Streptococcus pneumoniae. The strains carrying the slow-reacting PBP demonstrated a sensitivity to penicillin that was several hundred times lower than that of strains not carrying it. Spontaneous mutants with minimal inhibitory concentrations of penicillin of 20, 40, and 80 pug/ml were isolated from S. faecium ATCC 9790. They all showed a dramatic increase in the amount of slow-reacting PBP produced. Mutants with increased penicillin resistance were also isolated from wild-type strains of S. durans, S. faecalis, and S. faecium. All of them carried a greater amount of the slow-reacting PBP than that carried by the parent. Finally, it was found that resistant S. faecium ATCC 9790 mutants grew normally in the presence of penicillin concentrations that were far above that saturating all PBPs except PBP 5. Cell growth was, on the contrary, inhibited by a penicillin concentration that saturated the slow-reacting PBP by 90%. This penicillin dose was equal to the minimal inhibitory concentration.
The study suggests that nursing homes are a significant reservoir for MRSA. Statistical and PFGE analyses indicate a scenario where MRSA seems to be endemic and individual risk factors, namely recent hospitalizations and repeated antibiotic treatments, play a major role in the selection of drug-resistant organisms. Infection control measures should be coordinated among different health care settings, and the appropriate use of antibiotics has emerged as an important issue for improving the quality of care.
Ten clinical isolates of Enterococcusfaecalis were examined for susceptibility to the bactericidal activity of penicillin. Four of these had MBCs of penicillin equal to 2 to 4x the MIC, and six exhibited a paradoxical response to penicillin, i.e., the bactericidal activity of the anitibiotic had a concentration optimum at 2 to 4x the MIC and decreased significantly at concentrations above this. We found that the paradoxical response to penicillin was an intrinsic and stable property of a strain, but that its phenotypic expression was not homogeneous; only a fraction of the cell population that died at low concentrations was able to survive at high penicillin concentrations. The size of this fraction increased with increasing antibiotic concentration and reached a maximum in the late-log phase of growth. All 10 strains produced a lytic enzyme that was active on Micrococcus luteus heat-killed cells, whereas only some strains lysed E. faecalis heat-killed cells. Strains producing large amounts of the latter enzyme did not show the paradoxical response to penicillin, whereas mutants of these strains that lacked this enzymatic activity paradoxically responded to the antibiotic activity. In addition, from strains that showed paradoxical response to penicillin and produced only the enzyme that was active on M. luteus, it was possible to isolate mutants that were also capable of lysing E. faecalis cells and that were killed with similar efficiency by all concentrations above the MBC. On the basis of these findings, the paradoxical response to penicillin is explained as a property of certain strains of E. faecalis; this property is genetically characterized by alterations in synthesis or activity of one autolysin but phenotypically expressed only by a few cells that are in a particular physiological condition when exposed to high concentrations of antibiotics.
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