Journal Article

PUBDB-2025-05497

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Binding mode of Isoxazolyl Penicillins to a Class-A β-lactamase at ambient conditions

Gore, G.Extern* ; Prester, A. ; von Stetten, D.Extern* ; Bartels, K.CSSB*EMBL* ; Schulz, E. C. (Corresponding author)Extern*

2025
Macmillan Publishers Limited, part of Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s42004-025-01801-x  doi:10.3204/PUBDB-2025-05497

Abstract: 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.

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Contributing Institute(s):

1. Forschungsgruppe für strukturelle Dynamik (MPSD)

Research Program(s):

1. DFG project G:(GEPRIS)458246365 - Zeitaufgelöste Strukturanalysde der extended spectrum Beta-Lactamase CTX-M-14 (458246365) (458246365)
2. 899 - ohne Topic (POF4-899) (POF4-899)

Experiment(s):

1. No specific instrument

Appears in the scientific report 2025

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