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<p>Antimicrobial resistance is a critical global public health threat associated with high mortality rates worldwide. The efficacy of clinical antibiotics has declined precipitously with the emergence of multidrug resistance (MDR), driven by improper antimicrobial utilization, inadequate infection control, and rapid bacterial adaptation. The World Health Organization classifies MDR as a foremost public health priority. Pathogens such as Acinetobacter baumannii and Klebsiella pneumoniae are of particular concern due to their resistance to last-resort agents. While resistance is primarily mediated by carbapenem-hydrolyzing class D beta-lactamases (oxacillinases), other mechanisms—including efflux pump upregulation, porin modifications, and target alterations—contribute to this phenotype. Recent evidence indicates that single-point mutations can significantly modulate enzyme structure and catalytic efficiency. In this study, an integrated in silico approach was employed to investigate the structural and functional consequences of specific mutations in OXA-24 and OXA-48. The three-dimensional structures of wild-type and variant enzymes were modeled and refined using GalaxyRefine2 and the SAVES server. Protein–ligand interaction profiles were characterized via molecular docking with the Schrödinger GLIDE program and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) calculations across twelve beta-lactam antibiotics (amoxicillin, cefixime, cefepime, ceftaroline, cefiderocol, doripenem, imipenem, razupenem, tazobactam, tebipenem, thienamycin, and ticarcillin). To evaluate the stability, compactness, and conformational dynamics of the wild-type (OXA-24 and OXA-48) and variant (OXA-918 and OXA-244) systems, 250&#xa0;ns molecular dynamics (MD) simulations were performed. Trajectories were comprehensively analyzed for root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), hydrogen bonding occupancy, principal component analysis (PCA), dynamic cross-correlation matrices (DCCM), and free energy landscapes (FEL). The computational results demonstrated that the OXA-918 and OXA-244 variants display altered ligand-binding thermodynamics and localized conformational dynamics compared to their wild-type counterparts. These findings provide molecular-level insights into how single-point mutations modulate the structural topology and resistance profiles of class D beta-lactamases, offering a framework for future biochemical and in vitro kinetic validation.</p>

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In silico comparative analysis of OXA-918 and OXA-244 sequences suggests altered beta-lactam interaction profiles in Acinetobacter baumannii and Klebsiella pneumoniae

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月28日

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  • Most. Afrin Akter,
  • Maria Mulla Mim,
  • Tawsif Al Arian,
  • Mahbubul Kabir Himel,
  • Aparna Shil

摘要

Antimicrobial resistance is a critical global public health threat associated with high mortality rates worldwide. The efficacy of clinical antibiotics has declined precipitously with the emergence of multidrug resistance (MDR), driven by improper antimicrobial utilization, inadequate infection control, and rapid bacterial adaptation. The World Health Organization classifies MDR as a foremost public health priority. Pathogens such as Acinetobacter baumannii and Klebsiella pneumoniae are of particular concern due to their resistance to last-resort agents. While resistance is primarily mediated by carbapenem-hydrolyzing class D beta-lactamases (oxacillinases), other mechanisms—including efflux pump upregulation, porin modifications, and target alterations—contribute to this phenotype. Recent evidence indicates that single-point mutations can significantly modulate enzyme structure and catalytic efficiency. In this study, an integrated in silico approach was employed to investigate the structural and functional consequences of specific mutations in OXA-24 and OXA-48. The three-dimensional structures of wild-type and variant enzymes were modeled and refined using GalaxyRefine2 and the SAVES server. Protein–ligand interaction profiles were characterized via molecular docking with the Schrödinger GLIDE program and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) calculations across twelve beta-lactam antibiotics (amoxicillin, cefixime, cefepime, ceftaroline, cefiderocol, doripenem, imipenem, razupenem, tazobactam, tebipenem, thienamycin, and ticarcillin). To evaluate the stability, compactness, and conformational dynamics of the wild-type (OXA-24 and OXA-48) and variant (OXA-918 and OXA-244) systems, 250 ns molecular dynamics (MD) simulations were performed. Trajectories were comprehensively analyzed for root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), hydrogen bonding occupancy, principal component analysis (PCA), dynamic cross-correlation matrices (DCCM), and free energy landscapes (FEL). The computational results demonstrated that the OXA-918 and OXA-244 variants display altered ligand-binding thermodynamics and localized conformational dynamics compared to their wild-type counterparts. These findings provide molecular-level insights into how single-point mutations modulate the structural topology and resistance profiles of class D beta-lactamases, offering a framework for future biochemical and in vitro kinetic validation.