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<p><i>Salmonella</i> strains carrying the <i>bla</i><sub>CTX-M-55</sub> gene encoding the β-lactamase CTX-M-55 present markedly greater resistance to ceftazidime (CAZ) than those carrying the <i>bla</i><sub>CTX-M-14</sub> gene encoding CTX-M-14, but the structural basis remains unclear. In this study, we combined susceptibility testing, binding affinity measurement, molecular dynamics simulation, and site-directed point mutation to examine how CTX-M-55 enhances CAZ hydrolysis. Compared with CTX-M-14, CTX-M-55 conferred an eightfold higher minimum inhibitory concentration for CAZ and exhibited more than tenfold stronger CAZ binding affinity. Structural and simulation analyses revealed that CTX-M-55 possesses a larger and more hydrophobic active pocket that supports more rapid interactions with CAZ and forms a more stable binding environment, driven mainly by favorable van der Waals and solvation energies. Mutation analysis further revealed two functionally distinct classes of residues contributing to CAZ resistance. Asp-131 and Asn-132 represent functional determinants of CAZ hydrolysis in CTX-M-55, as their substitution disrupts the structure of the binding pocket and hinders the effective binding of the substrate. In contrast, Ser-272 acts as an optimized residue that strengthens the hydrolytic capacity of CTX-M-55 compared with that of CTX-M-14 by modulating CAZ accommodation within a stable pocket. Together, these results indicate that the stronger CAZ resistance of CTX-M-55 results from both a favorable pocket structure and specific residue effects, with Asp-131 and Asn-132 providing the basic hydrolysis capacity and Ser-272 playing an optimized role for CAZ. This work helps clarify the differences in CAZ resistance among the CTX-M family and points to pocket features that may be useful targets for inhibitor design.</p>

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Molecular determinants underlying enhanced ceftazidime resistance mediated by the β-lactamase CTX-M-55 compared with CTX-M-14

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月23日

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  • Wei Tan,
  • Lihua An,
  • Yifan Zhang,
  • Dongliang Hu,
  • Zhenfang Fu,
  • Shaowen Li,
  • Xianrong Meng

摘要

Salmonella strains carrying the blaCTX-M-55 gene encoding the β-lactamase CTX-M-55 present markedly greater resistance to ceftazidime (CAZ) than those carrying the blaCTX-M-14 gene encoding CTX-M-14, but the structural basis remains unclear. In this study, we combined susceptibility testing, binding affinity measurement, molecular dynamics simulation, and site-directed point mutation to examine how CTX-M-55 enhances CAZ hydrolysis. Compared with CTX-M-14, CTX-M-55 conferred an eightfold higher minimum inhibitory concentration for CAZ and exhibited more than tenfold stronger CAZ binding affinity. Structural and simulation analyses revealed that CTX-M-55 possesses a larger and more hydrophobic active pocket that supports more rapid interactions with CAZ and forms a more stable binding environment, driven mainly by favorable van der Waals and solvation energies. Mutation analysis further revealed two functionally distinct classes of residues contributing to CAZ resistance. Asp-131 and Asn-132 represent functional determinants of CAZ hydrolysis in CTX-M-55, as their substitution disrupts the structure of the binding pocket and hinders the effective binding of the substrate. In contrast, Ser-272 acts as an optimized residue that strengthens the hydrolytic capacity of CTX-M-55 compared with that of CTX-M-14 by modulating CAZ accommodation within a stable pocket. Together, these results indicate that the stronger CAZ resistance of CTX-M-55 results from both a favorable pocket structure and specific residue effects, with Asp-131 and Asn-132 providing the basic hydrolysis capacity and Ser-272 playing an optimized role for CAZ. This work helps clarify the differences in CAZ resistance among the CTX-M family and points to pocket features that may be useful targets for inhibitor design.