Roqunuzzaman, Md, Islam, Md Shariful, Supti, Sumaiya Jahan, Rifat, Mahbub Hasan, Islam, Mohammad Saiful, Ananna, Ummay Habiba, Tusher, Khalid Saifullah, Al-Mutairi, Aamal A., Zaki, Magdi E.A., Sarker, Subir, and Hosen, Md. Eram (2025) Fungal metabolite Ochratoxin A inhibits MrkD1P of multidrug-resistant Klebsiella pneumoniae: Integrated computational and in vitro validation. Journal of Computer Aided Molecular Design, 39. 81.

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Abstract

Multidrug-resistant (MDR) Klebsiella pneumoniae poses a significant global health concern, particularly in hospital setting where it causes severe and hard-to-treat infections. In this study, 329 fungal-derived compounds were screened for their potential to inhibit MrkD1P, a key fimbrial adhesin protein (PDB ID: 3U4K) involved in host tissue adhesion. Molecular docking analysis identified ochratoxin A (− 9.1 kcal/mol), bromadiolone (− 8.6 kcal/mol), and permethrin (− 8.2 kcal/mol) as top-performing candidates, exhibiting strong binding affinities and stable molecular interactions, including hydrogen bonding and hydrophobic contacts. These findings were reinforced by 100-nanosecond molecular dynamics (MD) simulations, which showed sustained ligand–protein stability, particularly for ochratoxin A. Free energy estimations using the MM/PBSA method further suggested the thermodynamic favourability of these interactions. Pharmacokinetic profiling (ADMET) indicated favourable absorption and distribution properties for all three compounds, with low toxicity predictions, though some hepatotoxicity was noted. Principal component analysis (PCA) demonstrated that ochratoxin A and permethrin induced substantial alterations in protein dynamics, suggesting ligand-specific structural effects. Experimental validation confirmed the antibacterial activity of ochratoxin A against K. pneumoniae, producing a 34 ± 0.67 mm inhibition zone at 100 µg/disc, surpassing ciprofloxacin (33 mm) with a MIC of 18.33 ± 0.72 µg/mL and MBC of 39.33 ± 1.36 µg/mL (p < 0.05). Collectively, these in silico and in vitro results highlight fungal metabolites, particularly ochratoxin A, as promising therapeutic leads against MDR K. pneumoniae. However, further in vivo investigations are required to establish their safety and clinical potential.

Item ID:	89361
Item Type:	Article (Research - C1)
ISSN:	1573-4951
Keywords:	Antibacterial activity, Dynamics, Fimbrial adhesin protein MrkD1P, Fungal metabolites, Klebsiella pneumoniae, Molecular docking, PCA analysis
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Copyright Information:	This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit h t t p://creativecommons.org/licenses/by/4.0/
Date Deposited:	28 Oct 2025 22:45
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