Staphylococcus aureus penicillin-binding protein 4 and intrinsic beta-lactam resistance

Henze, Uta; Berger‐Bächi, Brigitte

doi:10.1128/aac.39.11.2415

Cited by 65 publications

(41 citation statements)

References 50 publications

(35 reference statements)

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“…4C). Also, the ATP binding cassette protein upstream of, and in reverse orientation to, the pbp4 gene in S. aureus (5,8) was not present upstream of pbp4 in S. epidermidis.…”

Section: Resultsmentioning

confidence: 99%

Novel Non- mecA -Containing Staphylococcal Chromosomal Cassette Composite Island Containing pbp4 and tagF Genes in a Commensal Staphylococcal Species: a Possible Reservoir for Antibiotic Resistance Islands in Staphylococcus aureus

Mongkolrattanothai

Boyle

Murphy

et al. 2004

Antimicrob Agents Chemother

111

100

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Among methicillin-resistant Staphylococcus aureus isolates, a staphylococcal chromosomal cassette containing the mecA gene (SCCmec) is integrated into the chromosome at a unique site. SCCmec also contains unique ccrAB recombinase genes mediating its integration and excision from the genome and is flanked by characteristic left and right direct-and inverted-repeat sequences. A few non-mecA-containing SCC elements that have the other molecular features described above have recently been described. The origin of these cassettes is not clear. We have identified two new members of the SCC family integrated within orfX in Staphylococcus epidermidis strain ATCC 12228, neither of which carries mecA. One is a 57-kb element flanked by a unique 28-bp SCC direct repeat. It was called the SCC composite island (SCC-CI) because it carries a 19-kb SCC element (SCCpbp4) nested within it. SCCpbp4 contains pbp4 and tagF genes, as well as one pair of ccrAB genes (allotype 2) flanked by classical SCC-specific terminal repeats. External to SCCpbp4, SCC-CI contains a second pair of ccrAB genes (allotype 4), three IS431 elements, and genes mediating resistance to heavy metals. Genes mediating restriction-modification that may facilitate horizontal transfer are also present within SCC-CI, both within and outside SCCpbp4. Several novel arrangements of the SCC direct and inverted repeats were identified. Several long stretches of homology with other SCCs were found within and outside SCCpbp4. In view of the fact that SCC-CI was found in a commensal species, it may represent a reservoir for sequences involved in genetic shuffling between staphylococci and may contribute to the diversity found in SCC elements.

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“…4C). Also, the ATP binding cassette protein upstream of, and in reverse orientation to, the pbp4 gene in S. aureus (5,8) was not present upstream of pbp4 in S. epidermidis.…”

Section: Resultsmentioning

confidence: 99%

Novel Non- mecA -Containing Staphylococcal Chromosomal Cassette Composite Island Containing pbp4 and tagF Genes in a Commensal Staphylococcal Species: a Possible Reservoir for Antibiotic Resistance Islands in Staphylococcus aureus

Mongkolrattanothai

Boyle

Murphy

et al. 2004

Antimicrob Agents Chemother

111

100

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“…Consistent with this is the finding of Henze and Berger-Bachi (14), who isolated an S. aureus mutant that overexpressed PBP4. A sequence analysis of the pbpD promoter region in this strain (14) revealed a 90-bp deletion (nt 381 to 470 [ Fig. 1]) and an insertion of a single nucleotide (between nt 482 and 483 [ Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have demonstrated that PBP2a has reduced binding affinity for ␤-lactams (11,31,40), leading to the hypothesis that PBP2a takes over the biosynthetic functions of the normal PBPs when the bacteria encounter ␤-lactam antibiotics. Although PBP2a is essential for high-level methicillin resistance, a role for PBP4 in borderline methicillin-resistant strains, which lack PBP2a, has been well documented (1,4,14,39). These studies demonstrate that the overproduction or modification of PBP4 leads to increased resistance to methicillin.…”

mentioning

confidence: 99%

Transcription analysis of the Staphylococcus aureus gene encoding penicillin-binding protein 4

1997

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The high level of cross-linking found in Staphylococcus aureus peptidoglycan is dependent on the low-molecular-weight penicillin-binding protein PBP4. Recently, the PBP4 gene, pbpD, was cloned and shown to be adjacent to and divergently transcribed relative to the putative ABC-type transporter gene, abcA. Disruption of abcA (in strain KB400) was previously shown to result in heightened resistance to several antibiotics known to interact with PBP4, suggesting that the regulation of pbpD is affected by abcA. In this report, this hypothesis was confirmed by use of a Northern (RNA) blot analysis which revealed increased accumulation of pbpD-specific transcripts in KB400 compared to that in the wild-type strain, 8325-4. By using reverse-phase highperformance liquid chromatography to examine the structure of the peptidoglycan, it was demonstrated that the increased expression of pbpD resulted in an increased level of peptidoglycan cross-linking in the staphylococcal cell wall. Promoter fusion studies demonstrated that the abcA mutation caused approximately 7-fold and 100-fold increases in pbpD and abcA promoter activities, respectively. Primer extension experiments revealed that these genes have long, untranslated leader sequences that result in a transcriptional overlap of 80 bp. Interestingly, deletion of a 26-bp region containing an inverted repeat sequence resulted in the loss of expression from both the abcA and the pbpD promoters. These data provide evidence that abcA and pbpD are under the control of a common regulatory mechanism that may involve the transport function of the abcA gene product.Methicillin-sensitive strains of Staphylococcus aureus produce four penicillin-binding proteins (PBPs), 1 to 4, that are involved in the assembly of the cell wall peptidoglycan. Growth studies using cefotaxime and cephalexin, ␤-lactam antibiotics that preferentially interact with PBP2 and PBP3, respectively, have provided insight into the physiological roles of these PBPs (9). Exposure of S. aureus cells to cefotaxime resulted in extrusion of cytoplasm and cell lysis, while exposure to cephalexin resulted in cell enlargement and the cessation of septation (9). Based on these data, it was hypothesized that PBP2 and PBP3 are essential for cell viability and function as the primary peptidoglycan transpeptidase and a septation-associated transpeptidase, respectively (9). PBP4, the only low-molecular-weight PBP produced by S. aureus, has been shown to be involved in secondary cross-linking. Wyke et al. (41) reported that mutants lacking PBP4 contained a hypo-cross-linked cell wall, providing evidence that this protein, although nonessential, plays an important role in the high level of cell wall cross-linking seen in S. aureus. In agreement with this are the studies of Kozarich and Strominger (19) demonstrating that purified PBP4 is unique among the low-molecular-weight PBPs in that it possesses transpeptidase and carboxypeptidase activities.Methicillin-resistant S. aureus produces a fifth PBP, termed PBP2a, that is the prima...

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“…The contribution of the normal staphylococcal PBPs to methicillin resistance in a MC' background has not yet been investigated systematically. PBP4 overproduction [12], or alterations in the amount and/or kinetics of PBP2 and/or PBP4 [13,14] may contribute to increased resistance, and low level methicillin-resistant clinical isolates with altered methicillin binding affinities of PBPl and PBP2 and PBP4 overproduction have been reported [15]. There might be an additive effect between the staphylococcal PBPs and PBP2' in methicillin resistance.…”

Section: Discussionmentioning

confidence: 99%

Impact of sar and agr on methicillin resistance in Staphylococcus aureus

Durán

1996

FEMS Microbiology Letters

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The global regulators ugr and sar control expression of cell wall and extracellular proteins. Inactivation of either sar and/or agr in a typical heterogeneously methicillin-resistant Staphylococcus aureus resulted in a small but reproducible decrease in the number of cells in the subpopulation expressing high methicillin resistance. The amount of low affinity penicillin-binding protein PBP2', the prerequisite for methicillin resistance, was apparently not affected, however, a reduction in PBPl and PBP3 production was observed, suggesting that these resident PBPs of the cells might be involved somehow together with PBPZ' in high level methicillin resistance.

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Staphylococcus aureus penicillin-binding protein 4 and intrinsic beta-lactam resistance

Cited by 65 publications

References 50 publications

Novel Non- mecA -Containing Staphylococcal Chromosomal Cassette Composite Island Containing pbp4 and tagF Genes in a Commensal Staphylococcal Species: a Possible Reservoir for Antibiotic Resistance Islands in Staphylococcus aureus

Novel Non- mecA -Containing Staphylococcal Chromosomal Cassette Composite Island Containing pbp4 and tagF Genes in a Commensal Staphylococcal Species: a Possible Reservoir for Antibiotic Resistance Islands in Staphylococcus aureus

Transcription analysis of the Staphylococcus aureus gene encoding penicillin-binding protein 4

Impact of sar and agr on methicillin resistance in Staphylococcus aureus

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