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ORIGINAL RESEARCH article

Front. Cell. Infect. Microbiol.
Sec. Antibiotic Resistance and New Antimicrobial drugs
Volume 15 - 2025 | doi: 10.3389/fcimb.2025.1521391
This article is part of the Research Topic Advances in New Combinational Therapies for Treatment of MDR Pathogens View all 5 articles

Overcoming Beta-Lactam Resistance in Pseudomonas aeruginosa by Targeting Metallo-Beta-Lactamase VIM-1: A One-Microsecond Molecular Dynamics Simulation Study

Provisionally accepted
Mohammed Salleh M. Ardawi Mohammed Salleh M. Ardawi 1Samar A. Badreddine Samar A. Badreddine 2Muhammad Yasir Muhammad Yasir 3Aiah Khateb Aiah Khateb 3Safaa A. Turkistani Safaa A. Turkistani 4Ahmed Afandi Ahmed Afandi 5Samah O. Noor Samah O. Noor 6Adhari Alsulami Adhari Alsulami 1Vivek Dhar Dwivedi Vivek Dhar Dwivedi 7,8*Esam Ibraheem Azhar Esam Ibraheem Azhar 3*
  • 1 Fakeeh College of Medical Sciences, Jeddah, Saudi Arabia
  • 2 Soliman Fakeeh Hospital, Jeddah, Saudi Arabia
  • 3 Special Infectious Agents Unit, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, Makkah, Saudi Arabia
  • 4 Department of Medical Laboratory Sciences, Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia
  • 5 King Fahd Armed Forces Hospital, Jeddah, Saudi Arabia
  • 6 Faculty of Sciences, King Abdulaziz University, Jeddah, Makkah, Saudi Arabia
  • 7 Bioinformatics Research Division, Quanta Calculus, Greater Noida, India
  • 8 Saveetha Medical College & Hospital, Chennai, Tamil Nadu, India

The final, formatted version of the article will be published soon.

    Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative opportunistic pathogen with a high resistance to beta-lactam antibiotics, mainly due to the production of metallo-beta-lactamase VIM-1 (MBL-VIM-1) enzyme. This study aimed to identify new inhibitors targeting MBL-VIM-1 to restore the efficacy of beta-lactam antibiotics. Extensive screening of natural compounds from the COCONUT database was performed to identify the structural analogs of the existing inhibitor of the MBL-VIM-1 protein. The virtual screening process selected four top-performing compounds (CNP0390322, CNP03905695, CNP0079056, and CNP0338283) that exhibited promising docking scores. These compounds were then subjected to re-docking and one-microsecond molecular dynamics (MD) simulations to assess their binding stability and interactions within the MBL-VIM-1 active site. Finally, post-MD simulation calculations were employed to estimate the interaction strengths and compare the efficacy of these compounds against the reference inhibitor. The findings highlighted that these four potent MBL-VIM-1 inhibitors show superior binding affinity and stability, suggesting their potential to combat antibiotic resistance in P. aeruginosa. The identified compounds offer a promising avenue for developing novel therapeutics to restore the efficacy of beta-lactam antibiotics against resistant bacterial strains. Therefore, further in vitro and in vivo studies are warranted to validate their potential.

    Keywords: P. aeruginosa, metallo-beta-lactamase, VIM-1, beta-lactam antibiotics, Drug Discovery

    Received: 01 Nov 2024; Accepted: 08 Jan 2025.

    Copyright: © 2025 Ardawi, Badreddine, Yasir, Khateb, Turkistani, Afandi, Noor, Alsulami, Dwivedi and Azhar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Vivek Dhar Dwivedi, Bioinformatics Research Division, Quanta Calculus, Greater Noida, India
    Esam Ibraheem Azhar, Special Infectious Agents Unit, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, 22252, Makkah, Saudi Arabia

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