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<p>New Delhi metallo-β-lactamase (NDM)-producing enterobacterales infections pose significant challenges due to limited treatment options. Recently, a triple combination of ceftazidime/avibactam and aztreonam has been utilized to combat these infections. However, a four-amino-acid insertion in PBP3 and/or the ampC β-lactamase has been linked to the development of resistance to this triple combination in several recent investigations. To evaluate the effectiveness of cefiderocol and cefepime/tazobactam using both in-vitro and in-silico methods, this study examines current non-duplicate isolates of carbapenem-resistant <i>E. coli</i> (<i>n</i> = 40) and carbapenem-resistant <i>K. pneumoniae</i> (<i>n</i> = 40) derived from blood cultures. The MIC of cefepime/taniborbactam and cefiderocol was ascertained using the micro-broth dilution technique. Additionally, computational analysis was performed using molecular docking with AutoDock tools and dynamic simulation with GROMACS, followed by MM-PBSA analysis for a duration of 50&#xa0;ns. In MIC assays, cefiderocol and cefepime/taniborbactam showed minimal effectiveness against NDM-producing <i>K. pneumoniae</i> and <i>E. coli</i> that possessed OXA-48-like traits. However, both antibiotics showed strong affinity against OXA-48-like producers. Docking studies varied from −4.3 to −8.1&#xa0;kcal/mol, indicating a higher binding affinity and stronger hydrogen bond formation in OXA-48-like compared to NDM producers. All complexes exhibited stable conformational states, as indicated by analyses of the RMSD, RMSF, Rg, SASA, and hydrogen bond trajectories. Further evidence supports stable BL/BLI interactions within binding sites, mediated by PCA, FEL, and DCCM, as indicated by the binding free energy. Computational studies confirmed better binding affinity for both OXA-48-like and NDM. However, in-vitro studies demonstrated that cefepime/taniborbactam and cefiderocol represent viable alternative options, specifically for OXA-48-like producers<i>,</i> as their effectiveness is significantly compromised in the presence of NDM.</p>

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Evaluating Antibacterial Efficacy of Cefiderocol and Cefepime/Taniborbactam Against OXA-48-Like and NDM-Expressing Enterobacterales: An In-Vitro and In-Silico Approach

  • 期刊论文

  • 发表日期：

    2025年10月25日

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  • Mohanraj Gopikrishnan,
  • Sriroopreddy Ramireddy,
  • Yamuna Devi Bakathavatchalam,
  • Rinku Polachirakkal Varghese,
  • D. Thirumal Kumar,
  • Binesh Lal,
  • Abi Manesh,
  • Kamini Walia,
  • Balaji Veeraraghavan,
  • C. George Priya Doss

摘要

New Delhi metallo-β-lactamase (NDM)-producing enterobacterales infections pose significant challenges due to limited treatment options. Recently, a triple combination of ceftazidime/avibactam and aztreonam has been utilized to combat these infections. However, a four-amino-acid insertion in PBP3 and/or the ampC β-lactamase has been linked to the development of resistance to this triple combination in several recent investigations. To evaluate the effectiveness of cefiderocol and cefepime/tazobactam using both in-vitro and in-silico methods, this study examines current non-duplicate isolates of carbapenem-resistant E. coli (n = 40) and carbapenem-resistant K. pneumoniae (n = 40) derived from blood cultures. The MIC of cefepime/taniborbactam and cefiderocol was ascertained using the micro-broth dilution technique. Additionally, computational analysis was performed using molecular docking with AutoDock tools and dynamic simulation with GROMACS, followed by MM-PBSA analysis for a duration of 50 ns. In MIC assays, cefiderocol and cefepime/taniborbactam showed minimal effectiveness against NDM-producing K. pneumoniae and E. coli that possessed OXA-48-like traits. However, both antibiotics showed strong affinity against OXA-48-like producers. Docking studies varied from −4.3 to −8.1 kcal/mol, indicating a higher binding affinity and stronger hydrogen bond formation in OXA-48-like compared to NDM producers. All complexes exhibited stable conformational states, as indicated by analyses of the RMSD, RMSF, Rg, SASA, and hydrogen bond trajectories. Further evidence supports stable BL/BLI interactions within binding sites, mediated by PCA, FEL, and DCCM, as indicated by the binding free energy. Computational studies confirmed better binding affinity for both OXA-48-like and NDM. However, in-vitro studies demonstrated that cefepime/taniborbactam and cefiderocol represent viable alternative options, specifically for OXA-48-like producers, as their effectiveness is significantly compromised in the presence of NDM.