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<p>The rise of multidrug-resistant (MDR) <i>Pseudomonas aeruginosa</i> poses a significant threat in clinical settings due to its intricate antimicrobial resistance mechanism, biofilm formation, quorum sensing, and efflux pump-mediated antibiotic tolerance capability. The progressive decline in the efficacy of conventional antibiotics necessitates the development of new treatment strategies. Disrupting the Quorum sensing, a pivotal regulator of virulence and biofilm-associated resistance presents a promising anti-virulence strategy. An integrated Subtractive genomics and in silico drug discovery approach was applied to the complete proteome of <i>P. aeruginosa</i> JJPA01, excluding paralogous, human homologous, and non-essential proteins to identify virulence-associated targets. 27 pathogen-specific pathway proteins were identified, with <i>pqsH</i> (WP_003090354.1), a key monooxygenase in the PQS quorum-sensing system. Potential inhibitors for <i>pqsH</i> were identified using High-Throughput Virtual Screening (HTVS) on natural compounds from the COCONUT, CMNPD, MNPD, Seaweed, and Specs databases. The docking study identified five compounds with the best binding affinities, ranging from −&#xa0;6.6 to −&#xa0;7.7&#xa0;kcal/mol. However, only CNP0000215 and CNP0007440 exhibited higher binding affinity to the <i>pqsH</i> protein than the cofactor Flavine Adenine Dinucleotide. With its established role in Antimicrobial Resistance and Virulence, <i>pqsH</i> has been selected as a therapeutic target and CNP0000215 as a promising PQS inhibitor to disrupt biofilm formation and combat antimicrobial resistance. These findings lay the groundwork for the strategic design of novel anti-therapeutics offering a promising strategy to inhibit persistent infections and resistance mechanisms in <i>P. aeruginosa</i>.</p> Graphical abstract <p></p>

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Integrative genomics and structural bioinformatics uncovers AMR-associated drug targets and pqsH inhibitors in multidrug-resistant Pseudomonas aeruginosa JJPA01

  • 期刊论文

  • 发表日期：

    2025年9月25日

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  • Bhuvaneswari Narthanareeswaran,
  • Nagarajan Hemavathy,
  • Sampathkumar Ranganathan,
  • Shaslinah Nathar,
  • Chitra Jeyaraj Pandian,
  • Jeyaraman Jeyakanthan

摘要

The rise of multidrug-resistant (MDR) Pseudomonas aeruginosa poses a significant threat in clinical settings due to its intricate antimicrobial resistance mechanism, biofilm formation, quorum sensing, and efflux pump-mediated antibiotic tolerance capability. The progressive decline in the efficacy of conventional antibiotics necessitates the development of new treatment strategies. Disrupting the Quorum sensing, a pivotal regulator of virulence and biofilm-associated resistance presents a promising anti-virulence strategy. An integrated Subtractive genomics and in silico drug discovery approach was applied to the complete proteome of P. aeruginosa JJPA01, excluding paralogous, human homologous, and non-essential proteins to identify virulence-associated targets. 27 pathogen-specific pathway proteins were identified, with pqsH (WP_003090354.1), a key monooxygenase in the PQS quorum-sensing system. Potential inhibitors for pqsH were identified using High-Throughput Virtual Screening (HTVS) on natural compounds from the COCONUT, CMNPD, MNPD, Seaweed, and Specs databases. The docking study identified five compounds with the best binding affinities, ranging from − 6.6 to − 7.7 kcal/mol. However, only CNP0000215 and CNP0007440 exhibited higher binding affinity to the pqsH protein than the cofactor Flavine Adenine Dinucleotide. With its established role in Antimicrobial Resistance and Virulence, pqsH has been selected as a therapeutic target and CNP0000215 as a promising PQS inhibitor to disrupt biofilm formation and combat antimicrobial resistance. These findings lay the groundwork for the strategic design of novel anti-therapeutics offering a promising strategy to inhibit persistent infections and resistance mechanisms in P. aeruginosa.

Graphical abstract