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Publication Abstract from PubMed

Resistance to the extended-spectrum cephalosporin ceftriaxone in the pathogenic bacteria Neisseria gonorrhoeae is conferred by mutations in penicillin-binding protein 2 (PBP2), the lethal target of the antibiotic, but how these mutations exert their effect at the molecular level is unclear. Using solution NMR, X-ray crystallography, and isothermal titration calorimetry, we report that WT PBP2 exchanges dynamically between a low-affinity state with an extended beta3-beta4 loop conformation and a high-affinity state with an inward beta3-beta4 loop conformation. Histidine-514, which is located at the boundary of the beta4 strand, plays an important role during the exchange between these two conformational states. We also find that mutations present in PBP2 from H041, a ceftriaxone-resistant strain of N. gonorrhoeae, increase resistance to ceftriaxone by destabilizing the inward beta3-beta4 loop conformation or stabilizing the extended beta3-beta4 loop conformation to favor the low-affinity drug-binding state. These observations reveal a unique mechanism for ceftriaxone resistance, whereby mutations in PBP2 lower the proportion of target molecules in the high-affinity drug-binding state and thus reduce inhibition at lower drug concentrations.

Mutations in PBP2 from ceftriaxone-resistant Neisseria gonorrhoeae alter the dynamics of the beta3-beta4 loop to favor a low-affinity drug-binding state.,Fenton BA, Tomberg J, Sciandra CA, Nicholas RA, Davies C, Zhou P J Biol Chem. 2021 Oct;297(4):101188. doi: 10.1016/j.jbc.2021.101188. Epub 2021, Sep 13. PMID:34529975^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.