Roqunuzzaman Md, Islam Ariful, 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
Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, Bangladesh.
Department of Chemistry, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, 11623, Kingdom of Saudi Arabia.
J Comput Aided Mol Des. 2025 Sep 16;39(1):81. doi: 10.1007/s10822-025-00661-w.
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.
多重耐药（MDR）肺炎克雷伯菌对全球健康构成重大威胁，尤其是在医院环境中，它会引发严重且难以治疗的感染。在本研究中，对329种真菌衍生化合物进行了筛选，以评估它们抑制MrkD1P的潜力，MrkD1P是一种参与宿主组织黏附的关键菌毛黏附蛋白（PDB ID：3U4K）。分子对接分析确定赭曲霉毒素A（-9.1 kcal/mol）、溴敌隆（-8.6 kcal/mol）和氯菊酯（-8.2 kcal/mol）为表现最佳的候选物，它们表现出很强的结合亲和力和稳定的分子相互作用，包括氢键和疏水接触。100纳秒的分子动力学（MD）模拟强化了这些发现，该模拟显示配体-蛋白质稳定性持续存在，尤其是赭曲霉毒素A。使用MM/PBSA方法进行的自由能估计进一步表明了这些相互作用的热力学有利性。药代动力学分析（ADMET）表明这三种化合物都具有良好的吸收和分布特性，毒性预测较低，不过注意到有一些肝毒性。主成分分析（PCA）表明，赭曲霉毒素A和氯菊酯会引起蛋白质动力学的显著变化，表明存在配体特异性结构效应。实验验证证实了赭曲霉毒素A对肺炎克雷伯菌的抗菌活性，在100 μg/圆盘时产生34±0.67 mm的抑菌圈，超过环丙沙星（33 mm），其最低抑菌浓度（MIC）为18.33±0.72 μg/mL，最低杀菌浓度（MBC）为39.33±1.36 μg/mL（p<0.05）。总体而言，这些计算机模拟和体外实验结果突出了真菌代谢产物，尤其是赭曲霉毒素A，作为对抗多重耐药肺炎克雷伯菌的有前景的治疗先导物。然而，需要进一步的体内研究来确定它们的安全性和临床潜力。
