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<p>The predominant resistance mechanism observed in Gram-negative bacteria involves the production of <i>β</i>-lactamases, which catalyse the hydrolysis of <i>β</i>-lactam antibiotics, thereby rendering them ineffective. Although Isoxazolyl Penicillins have been available since the 1970s, there are currently no structures in complex with class-A <i>β</i>-lactamases available. Here we have analysed the structure of the clinically relevant <i>β</i>-lactamase CTX-M-14 from <i>Klebsiella pneumoniae</i> near physiological temperatures, via serial synchrotron crystallography. We demonstrate the acyl-enzyme intermediates of the catalytically impaired CTX-M-14 mutant E166A in complex with three Isoxazolyl-Penicillins: Oxacillin, Cloxacillin and Dicloxacillin. Structural comparisons of CTX-M-Penicillin complexes show that, while conserved active-site interactions are maintained, each Isoxazolyl-Penicillin adopts a distinct conformation. While the three derivatives differ only by one and two chlorine atoms, respectively, their conformational heterogeneity appears to be increased by chlorination of the phenyl ring.</p>

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Binding mode of Isoxazolyl Penicillins to a Class-A β-lactamase at ambient conditions

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月1日

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  • Gargi Gore,
  • Andreas Prester,
  • David von Stetten,
  • Kim Bartels,
  • Eike C. Schulz

摘要

The predominant resistance mechanism observed in Gram-negative bacteria involves the production of β-lactamases, which catalyse the hydrolysis of β-lactam antibiotics, thereby rendering them ineffective. Although Isoxazolyl Penicillins have been available since the 1970s, there are currently no structures in complex with class-A β-lactamases available. Here we have analysed the structure of the clinically relevant β-lactamase CTX-M-14 from Klebsiella pneumoniae near physiological temperatures, via serial synchrotron crystallography. We demonstrate the acyl-enzyme intermediates of the catalytically impaired CTX-M-14 mutant E166A in complex with three Isoxazolyl-Penicillins: Oxacillin, Cloxacillin and Dicloxacillin. Structural comparisons of CTX-M-Penicillin complexes show that, while conserved active-site interactions are maintained, each Isoxazolyl-Penicillin adopts a distinct conformation. While the three derivatives differ only by one and two chlorine atoms, respectively, their conformational heterogeneity appears to be increased by chlorination of the phenyl ring.