Crystal Structures of Penicillin-Binding Protein 3 (PBP3) from Methicillin-Resistant Staphylococcus aureus in the Apo and Cefotaxime‐Bound Forms

Yoshida, Hisashi; Kawai, Fumihiro; Obayashi, E.; Akashi, Satoko; Roper, David I.; Tame, J.R.H.; Park, Sam-Yong

doi:10.1016/j.jmb.2012.07.012

Cited by 51 publications

(39 citation statements)

References 51 publications

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“…Interestingly, all the mutations detected in pbp2 were located in the transpeptidase domain. A nonsense mutation was detected in pbp3 of strain SRB that led to a premature stop codon, abolishing the entire C-terminal transpeptidase domain of PBP 3 (38). All of our passaged strains showed at least two point mutations in PBP 4, making it a highly mutated candidate in our study (Table 3).…”

Section: Resultsmentioning

confidence: 79%

PBP 4 Mediates High-Level Resistance to New-Generation Cephalosporins in Staphylococcus aureus

Chan

Gilbert

Basuino

et al. 2016

Antimicrob Agents Chemother

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bStaphylococcus aureus is an important cause of both hospital-and community-associated methicillin-resistant S. aureus (MRSA) infections worldwide. ␤-Lactam antibiotics are the drugs of choice to treat S. aureus infections, but resistance to these and other antibiotics make treatment problematic. High-level ␤-lactam resistance of S. aureus has always been attributed to the horizontally acquired penicillin binding protein 2a (PBP 2a) encoded by the mecA gene. Here, we show that S. aureus can also express high-level resistance to ␤-lactams, including new-generation broad-spectrum cephalosporins that are active against methicillin-resistant strains, through an uncanonical core genome-encoded penicillin binding protein, PBP 4, a nonessential enzyme previously considered not to be important for staphylococcal ␤-lactam resistance. Our results show that PBP 4 can mediate high-level resistance to ␤-lactams.

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Section: Resultsmentioning

confidence: 79%

PBP 4 Mediates High-Level Resistance to New-Generation Cephalosporins in Staphylococcus aureus

Chan

Gilbert

Basuino

et al. 2016

Antimicrob Agents Chemother

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“…They participate in the late stages of PG biosynthesis catalyzing the transglycosylation and/or transpeptidation of precursors into the growing PG. The four native staphylococcal PBPs have been functionally and structurally scrutinized over the past 40 years (30)(31)(32)(33)(34)(35). MRSA strains possess an exogenous PBP with very low affinity for ␤-lactam antibiotics, namely, PBP2A.…”

Section: Discussionmentioning

confidence: 99%

The Staphylococcus aureus Chaperone PrsA Is a New Auxiliary Factor of Oxacillin Resistance Affecting Penicillin-Binding Protein 2A

Jousselin

Manzano

Biette

et al. 2016

Antimicrob Agents Chemother

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Expression of the methicillin-resistant S. aureus (MRSA) phenotype results from the expression of the extra penicillin-binding protein 2A (PBP2A), which is encoded by mecA and acquired horizontally on part of the SCCmec cassette. PBP2A can catalyze DD-transpeptidation of peptidoglycan (PG) because of its low affinity for ␤-lactam antibiotics and can functionally cooperate with the PBP2 transglycosylase in the biosynthesis of PG. Here, we focus upon the role of the membrane-bound PrsA foldase protein as a regulator of ␤-lactam resistance expression. Deletion of prsA altered oxacillin resistance in three different SCCmec backgrounds and, more importantly, caused a decrease in PBP2A membrane amounts without affecting mecA mRNA levels. The N-and C-terminal domains of PrsA were found to be critical features for PBP2A protein membrane levels and oxacillin resistance. We propose that PrsA has a role in posttranscriptional maturation of PBP2A, possibly in the export and/or folding of newly synthesized PBP2A. This additional level of control in the expression of the mecA-dependent MRSA phenotype constitutes an opportunity to expand the strategies to design anti-infective agents.

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“…(9)). The crystallographic structures of all of them are already known [23, 29–31], with the exception of PBP1, which is a close homologue of the protein PBP2× from Streptococcus pneumoniae [32]. Proteins PBP1–3 act as transpeptidases even though PBP2 is the only bifunctional enzyme identified in S. aureus .…”

Section: The Physiological Role Of the Allosteric Sitmentioning

confidence: 99%

The Allosteric Site for the Nascent Cell Wall in Penicillin-Binding Protein 2a: An Achilles’ Heel of Methicillin-Resistant Staphylococcus aureus

Acebron¹,

Chang²,

Mobashery³

et al. 2015

CMC

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The ability to resist the effect of a wide range of antibiotics makes methicillin-resistant Staphylococcus aureus (MRSA) a leading global human pathogen. A key determinant of resistance to β-lactam antibiotics in this organism is penicillin-binding protein 2a (PBP2a), an enzyme that catalyzes the crosslinking reaction between two adjacent peptide stems during the peptidoglycan biosynthesis. The recently published crystal structure of the complex of PBP2a with ceftaroline, a cephalosporin antibiotic that shows efficacy against MRSA, has revealed the allosteric site at 60-Å distance from the transpeptidase domain. Binding of ceftaroline to the allosteric site of PBP2a triggers conformational changes that lead to the opening of the active site from a closed conformation, where a second molecule of ceftaroline binds to give inhibition of the enzyme. The discovery of allostery in MRSA remains the only known example of such regulation of cell-wall biosynthesis and represents a new paradigm in fighting MRSA. This review summarizes the present knowledge of the allosteric mechanism, the conformational changes allowing PBP2a catalysis and the means by which some clinical strains have acquired resistance to ceftaroline by disrupting the allosteric mechanism.

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Crystal Structures of Penicillin-Binding Protein 3 (PBP3) from Methicillin-Resistant Staphylococcus aureus in the Apo and Cefotaxime‐Bound Forms

Cited by 51 publications

References 51 publications

PBP 4 Mediates High-Level Resistance to New-Generation Cephalosporins in Staphylococcus aureus

PBP 4 Mediates High-Level Resistance to New-Generation Cephalosporins in Staphylococcus aureus

The Staphylococcus aureus Chaperone PrsA Is a New Auxiliary Factor of Oxacillin Resistance Affecting Penicillin-Binding Protein 2A

The Allosteric Site for the Nascent Cell Wall in Penicillin-Binding Protein 2a: An Achilles’ Heel of Methicillin-Resistant Staphylococcus aureus

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