Fungal metabolite Ochratoxin A inhibits MrkD1P of multidrug-resistant Klebsiella pneumoniae: Integrated computational and in vitro validation

Journal Publication ResearchOnline@JCU
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;Hosen, Md. Eram
Subir Sarker
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.

Journal

Journal of Computer Aided Molecular Design

Publication Name

Journal of Computer Aided Molecular Design

Volume

39

ISBN/ISSN

1573-4951

Edition

N/A

Issue

N/A

Pages Count

20

Location

N/A

Publisher

Springer

Publisher Url

N/A

Publisher Location

N/A

Publish Date

N/A

Url

N/A

Date

N/A

EISSN

N/A

DOI

10.1007/s10822-025-00661-w