Scholarlink

<p>The rise of antimicrobial resistance underscores the urgent need for new antibiotics and innovative strategies to address this global health challenge. In the present study, the antibacterial potential of pyrazolo[3,4-<i>d</i>]pyrimidine-based compounds was evaluated by an assessment of their inhibition of the enzymatic activity of dihydrofolate reductase (DHFR) and their anti-virulence effects against resistant strains of <i>Pseudomonas aeruginosa</i> and <i>Staphylococcus aureus</i>. The findings reveal that pyrazolo[3,4-d]pyrimidine analogs, particularly 10b, 10e, and 10d, effectively inhibit the growth of several Gram-positive and Gram-negative bacteria, likely through DHFR enzyme inhibition. Additionally, in silico studies provided insights into the structure–activity relationship of the examined compounds and the preferred binding of the highest affinity candidates to the DHFR active site. Notably, the <b>10e</b> derivative exhibits significantly stronger DHFR binding affinity (scoring function: − 69.4888), substantially exceeding that of the reference compound trimethoprim (scoring function: − 18.7745). Targeting bacterial virulence offers a promising approach to developing antibacterial agents with a reduced risk of resistance. An in silico docking study identified potential candidates targeting quorum-sensing (QS) systems that regulate bacterial virulence. The molecular modeling study indicated that the insertion of pyrazolo[3,4-<i>d</i>]pyrimidines at the LasI and LasR-type QS biotargets of <i>P. aeruginosa</i> and the <i>S. aureus</i> ArgC histidine kinase ATP-binding domain led to a unique binding mode that is most likely the target for the observed significant anti-virulence effects of the examined compounds. These virtual findings were validated through complementary in vitro and in vivo experiments. In summary, the compounds examined in this study demonstrated significant antimicrobial, antibiofilm, and anti-virulence activity. While both DHFR inhibition and QS disruption have been studied separately, this study is unique in examining compounds that simultaneously target both mechanisms and demonstrating compounds with enhanced potency.</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

Effectiveness of Bioactive Pyrazolo[3,4-d]Pyrimidine-based Analogs as Both Antibacterial Agents Targeting the DHFR Enzyme and Anti-virulence Candidates Against Resistant Strains of Pseudomonas aeruginosa and Staphylococcus aureus

  • 期刊论文

  • 发表日期：

    2026年3月2日

查看全文
  • Ibrahim M. Salem,
  • Tarek S. Ibrahim,
  • Wael A. H. Hegazy

摘要

The rise of antimicrobial resistance underscores the urgent need for new antibiotics and innovative strategies to address this global health challenge. In the present study, the antibacterial potential of pyrazolo[3,4-d]pyrimidine-based compounds was evaluated by an assessment of their inhibition of the enzymatic activity of dihydrofolate reductase (DHFR) and their anti-virulence effects against resistant strains of Pseudomonas aeruginosa and Staphylococcus aureus. The findings reveal that pyrazolo[3,4-d]pyrimidine analogs, particularly 10b, 10e, and 10d, effectively inhibit the growth of several Gram-positive and Gram-negative bacteria, likely through DHFR enzyme inhibition. Additionally, in silico studies provided insights into the structure–activity relationship of the examined compounds and the preferred binding of the highest affinity candidates to the DHFR active site. Notably, the 10e derivative exhibits significantly stronger DHFR binding affinity (scoring function: − 69.4888), substantially exceeding that of the reference compound trimethoprim (scoring function: − 18.7745). Targeting bacterial virulence offers a promising approach to developing antibacterial agents with a reduced risk of resistance. An in silico docking study identified potential candidates targeting quorum-sensing (QS) systems that regulate bacterial virulence. The molecular modeling study indicated that the insertion of pyrazolo[3,4-d]pyrimidines at the LasI and LasR-type QS biotargets of P. aeruginosa and the S. aureus ArgC histidine kinase ATP-binding domain led to a unique binding mode that is most likely the target for the observed significant anti-virulence effects of the examined compounds. These virtual findings were validated through complementary in vitro and in vivo experiments. In summary, the compounds examined in this study demonstrated significant antimicrobial, antibiofilm, and anti-virulence activity. While both DHFR inhibition and QS disruption have been studied separately, this study is unique in examining compounds that simultaneously target both mechanisms and demonstrating compounds with enhanced potency.