Penicillin-binding proteins of penicillin-susceptible and intrinsically resistant Neisseria gonorrhoeae

Dougherty, Thomas J.; Koller, A E; Tomasz, Alexander

doi:10.1128/aac.18.5.730

Cited by 148 publications

(98 citation statements)

References 34 publications

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“…They may be related to strain differences or, possibly, to differences in the degree of methicillin resistance. Multiple PBP alterations have only been seen at relatively high levels of resistance as reported for PBPs IN METHICILLIN-RESISTANT S. AUREUS 735 intrinsically penicillin-resistant pneumococci (25) and gonococci (5).…”

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confidence: 98%

“…The phenotypic loss of antibiotic resistance observable in MR cultures during growth at pH 5 Table 1 summarizes some of the relevant properties of the MR and MS strains used in our studies. MR strain RUCUS 1112 which was chosen for detailed study showed some, but not all, of the pleiotrophic properties described in the literature for other MR isolates of S. aureus (16).…”

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confidence: 99%

“…When the cell concentrations reached ca. 5 x 108 colony-forming units per ml, each of these cultures was diluted back (0.1 ml into 10 ml of fresh prewarmed media) to initiate the following three subcultures: two TSB cultures at pH 7.0 plus one culture at pH 5 the bacteria exhibited high susceptibility to methicillin addition (Fig. 3A).…”

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Altered penicillin-binding proteins in methicillin-resistant strains of Staphylococcus aureus

Hartman¹,

Tomasz²

1981

Antimicrob Agents Chemother

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156

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The penicillin-binding proteins (PBPs) of a methicillin-resistant (MR) and a methicillin-susceptible (MS) Staphylococcus aureus were compared by various approaches involving the use of high-specific-activity [3H]penicillin as a reagent. The MR and MS strains were found to contain PBPs of the same number and electrophoretic mobilities. However, saturation of PBPs 1, 2, and 3 by methicillin in the MR strain required the use of several thousands of micrograms of antibiotic per milliliter, whereas 0.2 to 0.4 ,ug of methicillin per ml was sufficient to effectively compete with [3H]penicillin for the PBPs of the MS strain. Additional experiments indicate that these differences most likely reflect a greatly decreased affinity of the PBPs of the MR strain as compared to those of the MS strain. Shift of the pH of the culture medium of the MR strain from pH 7.0 to 5.2 resulted in an immediate drop in phenotypic resistance to methicillin (from a minimal inhibitory concentration value of 3,200 /Lg/ml at pH 7.0 to 0.8 ,ug/ml at pH 5.2). Examination of the methicillin affinities of PBPs in MR bacteria grown at pH 5.2 showed the presence of the same low-affinity PBPs as in bacteria grown at pH 7.0. Thus, the pH-dependent resensitization to methicillin cannot be explained by a parallel increase in the antibiotic affinities of the PBPs.Extensive studies on the nature of methicillin resistance in Staphylococcus aureus have led to the recognition of several pleimorphic properties in these mutants. These include reduced susceptibility to lysostaphin (17), deficiency in protein A (23), and a change in the net surface charge of the cells (9). In addition, variation in several growth parameters was found to have profound influence on the expression of methicillin resistance. Specifically, growth of resistant mutants at low pH (16,20) or in the presence of ethylenediaminetetraacetate (19) was shown to result in suppression of methicillin resistance. Furthermore, it was reported that, with at least some of the methicillin-resistant isolates, bacterial cultures appeared to be unable to fully express resistance if the culture was passed in drug-free medium and subsequently plated on the surface of agar plates containing methicillin. Addition of certain supplements to the agar such as high concentrations of sucrose or sodium chloride, or incubation of the plates at temperatures suboptimal for growth (30°C instead of 37°C), resulted in the recovery of an increased proportion of the population behaving as phenotypically methicillin-resistant bacteria (1, and for review 16). Serial passage in the presence of beta-lactams had the same effect (18), and the term "heterogeneity" was used to refer to this phenomenon.Biochemical studies on amino acid, amino sugar, and teichoic acid composition (24) failed to detect significant chemical differences between the methicillin-susceptible (MS) and -resistant (MR) staphylococci. These studies have led to an extensive characterization of the physiology of MR staphylococci. Nevertheless, the biochemical bas...

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confidence: 99%

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Altered penicillin-binding proteins in methicillin-resistant strains of Staphylococcus aureus

Hartman¹,

Tomasz²

1981

Antimicrob Agents Chemother

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156

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“…These antibiotics inhibit cell growth by binding covalently to the active sites of essential PBPs (1,4). Although deactivation by beta-lactamase is the most common mechanism of resistance to these drugs (6), mutational alteration resulting in low affinity of target PBPs for beta-lactam antibiotics has been proposed as another mechanism of resistance to these drugs in some bacterial species (7)(8)(9), including strains of methicillin-resistant Staphylococcus aureus (MRSA) (10)(11)(12)(13). For some bacterial strains this mechanism may be sufficient to explain the resistance observed, but for strains of MRSA it cannot account for their unique property of heterogeneous resistance (14,15).…”

Section: Introductionmentioning

confidence: 99%

Increased amounts of a novel penicillin-binding protein in a strain of methicillin-resistant Staphylococcus aureus exposed to nafcillin.

Chambers¹,

Hartman²,

Tomasz³

1985

J. Clin. Invest.

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104

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In addition to the four typical penicillin-binding proteins (PBPs), a strain of heterogeneously methicillin-resistant Staphylococcus aureus produced an extra 78-kD PBP (PBP 2a) that had a low affinity for nafcillin and penicillin. Addition of nafcillin to cultures of this strain caused a rapid increase in the amount of this PBP in cell membranes. This increase occurred at subinhibitory concentrations of drug within minutes of exposure, and was blocked by inhibitors of protein and RNA synthesis. This suggests that the synthesis of PBP 2a can be stimulated by exposure to beta-lactam antibiotics. This process may, in part, explain the heterogeneity in methicillin-resistant S. aureus.

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“…,3-lactam antibiotics act by binding to and inactivating PBPs, disrupting balanced PBP activity and resulting in bacterial death. Clinically important antibiotic resistance may be due to the emergence ofPBPs with a lower affinity for f3-lactams (8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Penicillin-binding protein inactivation by human neutrophil myeloperoxidase.

Rakita

Rosen²

1991

J. Clin. Invest.

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Myeloperoxidase (MPO), H202, and chloride comprise a potent antimicrobial system believed to contribute to the antimicrobial functions of neutrophils and monocytes. The mechanisms of microbicidal action are complex and not fully defined. This report describes the MPO-mediated inactivation, in Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa, of a class of cytoplasmic membrane enzymes (penicillinbinding proteins, PBPs) found in all eubacteria, that covalently bind 8l-lactam antibiotics to their active sites with loss of enzymatic activity. Inactivation of "essential" PBPs, including PBP1-PBP3 of E. coli, leads to unbalanced bacterial growth and cell death. MPO treatment of bacteria was associated with loss of penicillin binding by PBPs, strongly suggesting PBP inactivation. In E. coli, PBP inactivation was most rapid with PBP3, where the rate of decline in binding activity approximated but did not equal loss of viability. Changes in E. coli morphology (elongation), observed just before bacteriolysis, were consistent with early predominant inactivation of PBP3. We conclude that inactivation of essential PBPs is sufficient to account for an important fraction of MPO-mediated bactericidal action. This feature of MPO action interestingly recapitulates an antibacterial strategy evolved by 8-lactam-producing molds that must compete with bacteria for limited ecologic niches. (J. Clin. Invest. 1991. 88:750-754.)

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Penicillin-binding proteins of penicillin-susceptible and intrinsically resistant Neisseria gonorrhoeae

Cited by 148 publications

References 34 publications

Altered penicillin-binding proteins in methicillin-resistant strains of Staphylococcus aureus

Altered penicillin-binding proteins in methicillin-resistant strains of Staphylococcus aureus

Increased amounts of a novel penicillin-binding protein in a strain of methicillin-resistant Staphylococcus aureus exposed to nafcillin.

Penicillin-binding protein inactivation by human neutrophil myeloperoxidase.

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