ArticleBiochemistry2017
Alanine 501 Mutations in Penicillin-Binding Protein 2 from Neisseria gonorrhoeae: Structure, Mechanism, and Effects on Cephalosporin Resistance and Biological Fitness.
Article in Biochemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 51 citations in OpenAlex.
- Evidence for a Constrained Mutational Pathway to High-Level Spectinomycin Resistance inInternational journal of molecular sciences · 2026Article
- A penicillin-binding protein inhibitor series to target drug-resistant Neisseria gonorrhoeae.Nature microbiology · 2026Article
- Clonal Expansion ofInfection and drug resistance · 2026Article
- Whole genome sequencing of Neisseria gonorrhoeae among key populations in two cities of Bangladesh reveals genomic diversity and stable antimicrobial resistance.BMC infectious diseases · 2025Article
- Molecular Detection of Mutations in theTropical medicine and infectious disease · 2025Article
- Management and prevention of Neisseria meningitidis and Neisseria gonorrhoeae infections in the context of evolving antimicrobial resistance trends.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2025Review
- A new class of penicillin-binding protein inhibitors to address drug-resistantbioRxiv : the preprint server for biology · 2024Article
- Multigeographic clinical assessment of a molecular diagnostic assay for detection of key codons to predict decreased susceptibility or resistance to cephalosporins inAntimicrobial agents and chemotherapy · 2024Article
- Differential contribution of PBP occupancy and efflux on the effectiveness of β-lactams at their target site in clinical isolates of Neisseria gonorrhoeae.PLoS pathogens · 2024Article
- Molecular Basis of Influence of A501X Mutations in Penicillin-Binding Protein 2 ofInternational journal of molecular sciences · 2024Article
- Characterizing the diversity and commensal origins ofMicrobial genomics · 2024Article
- Loop-Mediated Isothermal Amplification Assay for Identifying Neisseria gonorrhoeae NonmosaicMicrobiology spectrum · 2022Article
- Molecular Mechanisms of Drug Resistance and Epidemiology of Multidrug-Resistant Variants ofInternational journal of molecular sciences · 2022Review
- Pharmacodynamics of Ceftriaxone, Ertapenem, Fosfomycin and Gentamicin inAntibiotics (Basel, Switzerland) · 2022Article
- Article
- Phylogenomic analysis reveals persistence of gonococcal strains with reduced-susceptibility to extended-spectrum cephalosporins and mosaic penA-34.Nature communications · 2021Article
- Emergence of a Neisseria gonorrhoeae clone with reduced cephalosporin susceptibility between 2014 and 2019 in Amsterdam, The Netherlands, revealed by genomic population analysis.The Journal of antimicrobial chemotherapy · 2021Article
- Article
- Antibiotic resistance among invasive Neisseria meningitidis isolates in England, Wales and Northern Ireland (2010/11 to 2018/19).PloS one · 2021Article
- Sudden emergence of aMicrobial genomics · 2020Article
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
Resistance of Neisseria gonorrhoeae to expanded-spectrum cephalosporins such as ceftriaxone and cefixime has increased markedly in the past decade. The primary cephalosporin resistance determinant is a mutated penA gene, which encodes the essential peptidoglycan transpeptidase, penicillin-binding protein 2 (PBP2). Decreased susceptibility and resistance can be conferred by mosaic penA alleles containing upward of 60 amino acid changes relative to wild-type PBP2, or by nonmosaic alleles with relatively few mutations, the most important of which occurs at Ala501 located near the active site of PBP2. Recently, fully cefixime- and ceftriaxone-resistant clinical isolates that harbored a mosaic penA allele with an A501P mutation were identified. To examine the potential of mutations at Ala501 to increase resistance to expanded-spectrum cephalosporins, we randomized codon 501 in a mosaic penA allele and transformed N. gonorrhoeae to increased cefixime resistance. Interestingly, only five substitutions of Ala501 (A501V, A501T, A501P, A501R, and A501S) that increased resistance and preserved essential transpeptidase function were isolated. To understand their structural implications, these mutations were introduced into the nonmosaic PBP2-6140CT, which contains four C-terminal mutations present in PBP2 from the penicillin-resistant strain FA6140. The crystal structure of PBP2-6140CT-A501T was determined and revealed ordering of a loop near the active site and a new hydrogen bond involving Thr501 that connects the loop and the SxxK conserved active site motif. The structure suggests that increased rigidity in the active site region is a mechanism for cephalosporin resistance mediated by Ala501 mutations in PBP2.
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