Scholarlink

<p>The rise of resistance to fourth-generation cephalosporin in <i>Pseudomonas aeruginosa</i> (<i>P. aeruginosa</i>) is a global concern. The resistance is largely driven by variants of chromosomally encoded AmpC β-lactamase, known as <i>Pseudomonas</i>-derived cephalosporinase (PDC), which arise from the mutations in the <i>ampC</i> gene. In addition, alteration in <i>dacB</i>, which encode the penicillin-binding protein 4 (PBP4), can lead to the overexpression of <i>ampC</i>, thereby contributing to β-lactam resistance. Present work analyzed 208 clinical isolates of <i>P. aeruginosa</i> using whole-genome sequencing (WGS) and detected multiple nonsynonymous single nucleotide polymorphisms (nsSNPs), such as Y264C, G444D, and a double mutation (A394P-T428P). All nsSNPs were predicted to be deleterious by several prediction program. Molecular dynamics (MD) simulations suggested that these substitutions destabilize PBP4, increase structural flexibility, and contribute to the resistance mechanism, which favored their selection. To determine the effective therapeutics against these mutations, molecular docking was conducted with various antibiotics. Cefoperazone exhibited the highest binding affinity (-7.3&#xa0;kcal/mol) among multiple PBP4 variants. The Molecular dynamics (MD) simulations and Molecular Mechanics Poisson Boltzmann Surface Area calculations (MMPBSA) further confirmed the favorable interactions between cefoperazone and PBP4 variants. <i>In vitro</i> MIC analyses supported these findings, indicating that cefoperazone displayed significant activity against clinical <i>dacB</i> mutants of <i>P. aeruginosa</i>. The study offers structural insight of <i>dacB</i> variants leading to antibiotic resistance and emphasizes the need to prioritize specific antibiotics to address the challenges arising from protein mutations.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Genomic and structural analysis of dacB variants associated with cephalosporin resistance in Pseudomonas aeruginosa

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月4日

查看全文
  • Shalini Mathpal,
  • Maruthan Karthik,
  • Tushar Joshi,
  • Vishnukumar Ramesh,
  • Kamini Walia,
  • Karthik Gunasekaran,
  • Balaji Veeraraghavan,
  • Sudha Ramaiah,
  • Anand Anbarasu

摘要

The rise of resistance to fourth-generation cephalosporin in Pseudomonas aeruginosa (P. aeruginosa) is a global concern. The resistance is largely driven by variants of chromosomally encoded AmpC β-lactamase, known as Pseudomonas-derived cephalosporinase (PDC), which arise from the mutations in the ampC gene. In addition, alteration in dacB, which encode the penicillin-binding protein 4 (PBP4), can lead to the overexpression of ampC, thereby contributing to β-lactam resistance. Present work analyzed 208 clinical isolates of P. aeruginosa using whole-genome sequencing (WGS) and detected multiple nonsynonymous single nucleotide polymorphisms (nsSNPs), such as Y264C, G444D, and a double mutation (A394P-T428P). All nsSNPs were predicted to be deleterious by several prediction program. Molecular dynamics (MD) simulations suggested that these substitutions destabilize PBP4, increase structural flexibility, and contribute to the resistance mechanism, which favored their selection. To determine the effective therapeutics against these mutations, molecular docking was conducted with various antibiotics. Cefoperazone exhibited the highest binding affinity (-7.3 kcal/mol) among multiple PBP4 variants. The Molecular dynamics (MD) simulations and Molecular Mechanics Poisson Boltzmann Surface Area calculations (MMPBSA) further confirmed the favorable interactions between cefoperazone and PBP4 variants. In vitro MIC analyses supported these findings, indicating that cefoperazone displayed significant activity against clinical dacB mutants of P. aeruginosa. The study offers structural insight of dacB variants leading to antibiotic resistance and emphasizes the need to prioritize specific antibiotics to address the challenges arising from protein mutations.