Inhibition of Acinetobacter-Derived Cephalosporinase: Exploring the Carboxylate Recognition Site Using Novel β-Lactamase Inhibitors
[2];
[1];
[4];
- Univ. of Modena and Reggio Emilia (Italy)
- Grand Valley State Univ., Allendale, MI (United States)
- Case Western Reserve Univ., Cleveland, OH (United States)
- Louis Stokes Cleveland Dept. of Veterans Affairs Medical Center, Cleveland, OH (United States); Case Western Reserve Univ., Cleveland, OH (United States)
Boronic acids are attracting a lot of attention as β-lactamase inhibitors, and in particular, compound S02030 (Ki = 44 nM) proved to be a good lead compound against ADC-7 (Acinetobacter-derived cephalosporinase), one of the most significant resistance determinants in A. baumannii. The atomic structure of the ADC-7/S02030 complex highlighted the importance of critical structural determinants for recognition of the boronic acids. Herein, to elucidate the role in recognition of the R2-carboxylate, which mimics the C3/C4 found in β-lactams, we designed, synthesized, and characterized six derivatives of S02030 (3a). Out of the six compounds, the best inhibitors proved to be those with an explicit negative charge (compounds 3a–c, 3h, and 3j, Ki = 44–115 nM), which is in contrast to the derivatives where the negative charge is omitted, such as the amide derivative 3d (Ki = 224 nM) and the hydroxyamide derivative 3e (Ki = 155 nM). To develop a structural characterization of inhibitor binding in the active site, the X-ray crystal structures of ADC-7 in a complex with compounds 3c, SM23, and EC04 were determined. All three compounds share the same structural features as in S02030 but only differ in the carboxy-R2 side chain, thereby providing the opportunity of exploring the distinct binding mode of the negatively charged R2 side chain. This cephalosporinase demonstrates a high degree of versatility in recognition, employing different residues to directly interact with the carboxylate, thus suggesting the existence of a “carboxylate binding region” rather than a binding site in ADC enzymes. As a result, this class of compounds was tested against resistant clinical strains of A. baumannii and are effective at inhibiting bacterial growth in conjunction with a β-lactam antibiotic.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- Cleveland Dept. of Veterans Affairs, the Veterans Affairs Merit Review Program; National Inst. of Allergy and Infectious Diseases of the National Inst. of Health
- Grant/Contract Number:
- 1I01BX001974; R01AI063517; R01AI100560
- OSTI ID:
- 1433692
- Journal Information:
- ACS Infectious Diseases, Vol. 4, Issue 3; ISSN 2373-8227
- Publisher:
- American Chemical Society (ACS)Copyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Web of Science
Deciphering the Evolution of Cephalosporin Resistance to Ceftolozane-Tazobactam in Pseudomonas aeruginosa
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journal | December 2018 |
Exploring Additional Dimensions of Complexity in Inhibitor Design for Serine β-Lactamases: Mechanistic and Intra- and Inter-molecular Chemistry Approaches
|
journal | April 2018 |
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