Characterization of Interactions between CTX-M-15 and Clavulanic Acid, Desfuroylceftiofur, Ceftiofur, Ampicillin, and Nitrocefin
Abstract
Cefotaximase-Munich (CTX-M) extended-spectrum beta-lactamases (ESBLs) are commonly associated with Gram-negative, hospital-acquired infections worldwide. Several beta-lactamase inhibitors, such as clavulanate, are used to inhibit the activity of these enzymes. To understand the mechanism of CTX-M-15 activity, we have determined the crystal structures of CTX-M-15 in complex with two specific classes of beta-lactam compounds, desfuroylceftiofur (DFC) and ampicillin, and an inhibitor, clavulanic acid. The crystal structures revealed that Ser70 and five other residues (Lys73, Tyr105, Glu166, Ser130, and Ser237) participate in catalysis and binding of those compounds. Based on analysis of steady-state kinetics, thermodynamic data, and molecular docking to both wild-type and S70A mutant structures, we determined that CTX-M-15 has a similar affinity for all beta-lactam compounds (ceftiofur, nitrocefin, DFC, and ampicillin), but with lower affinity for clavulanic acid. A catalytic mechanism for tested β-lactams and two-step inhibition mechanism of clavulanic acid were proposed. CTX-M-15 showed a higher activity toward DFC and nitrocefin, but significantly lower activity toward ampicillin and ceftiofur. The interaction between CTX-M-15 and both ampicillin and ceftiofur displayed a higher entropic but lower enthalpic effect, compared with DFC and nitrocefin. DFC, a metabolite of ceftiofur, displayed lower entropy and higher enthalpy than ceftiofur. This finding suggests that compounds containingmore »
- Publication Date:
- Research Org.:
- Washington State Univ., Pullman, WA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); Murdock Charitable Trust
- OSTI Identifier:
- 1903868
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Accepted Manuscript
- Journal Name:
- International Journal of Molecular Sciences (Online)
- Additional Journal Information:
- Journal Name: International Journal of Molecular Sciences (Online); Journal Volume: 23; Journal Issue: 9; Journal ID: ISSN 1422-0067
- Publisher:
- MDPI
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; antimicrobial resistance; β-lactamase; CTX-M-15; inhibitor; antibiotic; β-lactam compounds; crystal structure; inhibition mechanism
Citation Formats
Ahmadvand, Parvaneh, Avillan, Johannetsy J., Lewis, Jacob A., Call, Douglas R., and Kang, ChulHee. Characterization of Interactions between CTX-M-15 and Clavulanic Acid, Desfuroylceftiofur, Ceftiofur, Ampicillin, and Nitrocefin. United States: N. p., 2022.
Web. doi:10.3390/ijms23095229.
Ahmadvand, Parvaneh, Avillan, Johannetsy J., Lewis, Jacob A., Call, Douglas R., & Kang, ChulHee. Characterization of Interactions between CTX-M-15 and Clavulanic Acid, Desfuroylceftiofur, Ceftiofur, Ampicillin, and Nitrocefin. United States. https://doi.org/10.3390/ijms23095229
Ahmadvand, Parvaneh, Avillan, Johannetsy J., Lewis, Jacob A., Call, Douglas R., and Kang, ChulHee. Sat .
"Characterization of Interactions between CTX-M-15 and Clavulanic Acid, Desfuroylceftiofur, Ceftiofur, Ampicillin, and Nitrocefin". United States. https://doi.org/10.3390/ijms23095229. https://www.osti.gov/servlets/purl/1903868.
@article{osti_1903868,
title = {Characterization of Interactions between CTX-M-15 and Clavulanic Acid, Desfuroylceftiofur, Ceftiofur, Ampicillin, and Nitrocefin},
author = {Ahmadvand, Parvaneh and Avillan, Johannetsy J. and Lewis, Jacob A. and Call, Douglas R. and Kang, ChulHee},
abstractNote = {Cefotaximase-Munich (CTX-M) extended-spectrum beta-lactamases (ESBLs) are commonly associated with Gram-negative, hospital-acquired infections worldwide. Several beta-lactamase inhibitors, such as clavulanate, are used to inhibit the activity of these enzymes. To understand the mechanism of CTX-M-15 activity, we have determined the crystal structures of CTX-M-15 in complex with two specific classes of beta-lactam compounds, desfuroylceftiofur (DFC) and ampicillin, and an inhibitor, clavulanic acid. The crystal structures revealed that Ser70 and five other residues (Lys73, Tyr105, Glu166, Ser130, and Ser237) participate in catalysis and binding of those compounds. Based on analysis of steady-state kinetics, thermodynamic data, and molecular docking to both wild-type and S70A mutant structures, we determined that CTX-M-15 has a similar affinity for all beta-lactam compounds (ceftiofur, nitrocefin, DFC, and ampicillin), but with lower affinity for clavulanic acid. A catalytic mechanism for tested β-lactams and two-step inhibition mechanism of clavulanic acid were proposed. CTX-M-15 showed a higher activity toward DFC and nitrocefin, but significantly lower activity toward ampicillin and ceftiofur. The interaction between CTX-M-15 and both ampicillin and ceftiofur displayed a higher entropic but lower enthalpic effect, compared with DFC and nitrocefin. DFC, a metabolite of ceftiofur, displayed lower entropy and higher enthalpy than ceftiofur. This finding suggests that compounds containing amine moiety (e.g., ampicillin) and the furfural moiety (e.g., ceftiofur) could hinder the hydrolytic activity of CTX-M-15.},
doi = {10.3390/ijms23095229},
journal = {International Journal of Molecular Sciences (Online)},
number = 9,
volume = 23,
place = {United States},
year = {Sat May 07 00:00:00 EDT 2022},
month = {Sat May 07 00:00:00 EDT 2022}
}
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