A Highly Conserved Interaction Involving the Middle Residue of the SXN Active-Site Motif Is Crucial for Function of Class B Penicillin-Binding Proteins: Mutational and Computational Analysis of PBP 2 from <i>N. gonorrhoeae</i>

Tomberg, Joshua; Temple, Brenda; Fedarovich, Alena; Davies, Christopher; Nicholas, Robert A.

doi:10.1021/bi2017987

Cited by 16 publications

(31 citation statements)

References 54 publications

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“…In the absence of a crystal structure of PBP2 containing the Asp345a insertion, the impact of this mutation is not totally evident, but most likely it is more significant than the C-terminal substitutions. Notably, only an aspartate insertion confers resistance (195), and consistent with this, only an aspartate insertion is observed in clinical gonococcal strains (190). This might suggest that only an insertion of aspartate, not closely related amino acids, such as glutamate or asparagine, can discriminate against ␤-lactam antimicrobials without abolishing the PBP2 transpeptidase activity essential for viability (196).…”

Section: Penicillin Resistancementioning

confidence: 53%

Antimicrobial Resistance in Neisseria gonorrhoeae in the 21st Century: Past, Evolution, and Future

2014

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SUMMARY Neisseria gonorrhoeae is evolving into a superbug with resistance to previously and currently recommended antimicrobials for treatment of gonorrhea, which is a major public health concern globally. Given the global nature of gonorrhea, the high rate of usage of antimicrobials, suboptimal control and monitoring of antimicrobial resistance (AMR) and treatment failures, slow update of treatment guidelines in most geographical settings, and the extraordinary capacity of the gonococci to develop and retain AMR, it is likely that the global problem of gonococcal AMR will worsen in the foreseeable future and that the severe complications of gonorrhea will emerge as a silent epidemic. By understanding the evolution, emergence, and spread of AMR in N. gonorrhoeae , including its molecular and phenotypic mechanisms, resistance to antimicrobials used clinically can be anticipated, future methods for genetic testing for AMR might permit region-specific and tailor-made antimicrobial therapy, and the design of novel antimicrobials to circumvent the resistance problems can be undertaken more rationally. This review focuses on the history and evolution of gonorrhea treatment regimens and emerging resistance to them, on genetic and phenotypic determinants of gonococcal resistance to previously and currently recommended antimicrobials, including biological costs or benefits; and on crucial actions and future advances necessary to detect and treat resistant gonococcal strains and, ultimately, retain gonorrhea as a treatable infection.

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Section: Penicillin Resistancementioning

confidence: 53%

Antimicrobial Resistance in Neisseria gonorrhoeae in the 21st Century: Past, Evolution, and Future

2014

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“…S6, C and D). Although the sequence is not conserved, analogous structures to the L1 loop can be found in class A, B, and C PBPs and perturbation of this loop has been shown to play a role in ␤-lactam resistance (30,38,39). Notably, PBP2x from a highly mutated, penicillin-resistant strain of S. pneumoniae PBP2x, was also found to have variation in positioning of the SXN motif with the serine hydroxyl displaced away from the active site when compared with penicillin-sensitive PBP2x variants (40).…”

Section: Discussionmentioning

confidence: 99%

“…3). Although it has been suggested that this motif plays a role in deacylation in the structurally similar PBP5 of E. coli (30,36,37), perturbation of the SXN motif in PBP2, a transpeptidase from Neisseria gonorrheae, has been previously shown to reduce penicillin acylation rates (39). Future work is needed to determine the individual rate constants of acylation and deacylation in PBP4 and PBP4 CRB to better understand the role of the displaced and/or dynamic motion of the SXN motif in S. aureus PBP4 and the general resistance phenomenon it mediates.…”

Section: Analysis Of S Aureus Pbp4 Structure and Kineticsmentioning

confidence: 99%

Structural and kinetic analyses of penicillin-binding protein 4 (PBP4)-mediated antibiotic resistance in Staphylococcus aureus

Alexander¹,

Chatterjee

Hamilton

et al. 2018

Journal of Biological Chemistry

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Edited by Chris Whitfield Methicillin-resistant Staphylococcus aureus (MRSA) causes serious community-acquired and nosocomial infections worldwide. MRSA strains are resistant to a variety of antibiotics, including the classic penicillin and cephalosporin classes of ␤-lactams, making them intractable to treatment. Although ␤-lactam resistance in MRSA has been ascribed to the acquisition and activity of penicillin-binding protein 2a (PBP2a, encoded by mecA), it has recently been observed that resistance can also be mediated by penicillin-binding protein 4 (PBP4). Previously, we have shown that broad-spectrum ␤-lactam resistance can arise following serial passaging of a mecA-negative COL strain of S. aureus, creating the CRB strain. This strain has two missense mutations in pbp4 and a mutation in the pbp4 promoter, both of which play an instrumental role in ␤-lactam resistance. To better understand PBP4's role in resistance, here we have characterized its kinetics and structure with clinically relevant ␤-lactam antibiotics. We present the first crystallographic PBP4 structures of apo and acyl-enzyme intermediate forms complexed with three late-generation ␤-lactam antibiotics: ceftobiprole, ceftaroline, and nafcillin. In parallel, we characterized the structural and kinetic effects of the PBP4 mutations present in the CRB strain. Localized within the transpeptidase active-site cleft, the two substitutions appear to have different effects depending on the drug. With ceftobiprole, the missense mutations impaired the K m value 150-fold, decreasing the proportion of inhibited PBP4. However, ceftaroline resistance appeared to be mediated by other factors, possibly including mutation of the pbp4 promoter. Our findings provide evidence that S. aureus CRB has at least two PBP4-mediated resistance mechanisms.

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“…Note that residues 504 and 510 are in the β3–β4 loop. Flexibility of this loop has been linked to β-lactam resistance in PBP2x from S. pneumoniae [51]. …”

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confidence: 99%

Resistance to β-Lactams in Neisseria ssp Due to Chromosomally Encoded Penicillin-Binding Proteins

2016

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Neisseria meningitidis and Neisseria gonorrhoeae are human pathogens that cause a variety of life-threatening systemic and local infections, such as meningitis or gonorrhoea. The treatment of such infection is becoming more difficult due to antibiotic resistance. The focus of this review is on the mechanism of reduced susceptibility to penicillin and other β-lactams due to the modification of chromosomally encoded penicillin-binding proteins (PBP), in particular PBP2 encoded by the penA gene. The variety of penA alleles and resulting variant PBP2 enzymes is described and the important amino acid substitutions are presented and discussed in a structural context.

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A Highly Conserved Interaction Involving the Middle Residue of the SXN Active-Site Motif Is Crucial for Function of Class B Penicillin-Binding Proteins: Mutational and Computational Analysis of PBP 2 from N. gonorrhoeae

Cited by 16 publications

References 54 publications

Antimicrobial Resistance in Neisseria gonorrhoeae in the 21st Century: Past, Evolution, and Future

Antimicrobial Resistance in Neisseria gonorrhoeae in the 21st Century: Past, Evolution, and Future

Structural and kinetic analyses of penicillin-binding protein 4 (PBP4)-mediated antibiotic resistance in Staphylococcus aureus

Resistance to β-Lactams in Neisseria ssp Due to Chromosomally Encoded Penicillin-Binding Proteins

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