- Both Boronic inhibitors tested were effective in inhibiting ADC-7. 
- When tested with ADC-7 expressing bacteria, they observed excellent inhibition of ADC-7 when combined with beta-lactam antibiotics. 


Potential Inhibitors of Beta-Lactamases 

- Position of the R1 side chain is similar to that how beta-lactam antibiotics bind 
- Key residues were identified that are indicative of key binding areas the beta-lactam antibiotics bind.
- Variability was observed in the R2 region, they did not fully explain the importance of the R2 side-chain. However, they discovered an important residue (Arg340) that could be important in the binding of inhibitors to the beta-lactamase enzyme, ADC-7. 
- Both inhibitors were successful in binding the ADC-7.


Binding of Boronic Inhibitors

- Discovery of inhibitors that are promising when acting with antibiotics.
- Opportunity to create library of inhibitors based on changing substituents on the boronic inhibitors.
- These inhibitors do not resemble beta-lactams: high affinity binding is promising to see. 
- ID of key residues that are important for ideal interactions for inhibitors.


Summary: What is possible with these inhibitors?

- From identifying the X-ray Crystal structure of the beta-lactamase (ADC-7), boronic acid transition state inhibitors (BATSIs) were tested – these are inhibitors with a basis for inhibition properties against ADC-7. 
- They do not have the beta-lactam ring.

Grand Valley State University

- Current BLIs do not halt activity enough for the antibiotic to reach its target. 
- Because the structures contain the beta-lactam ring, they are more easily disrupted and the beta-lactamase can hydrolyze it just like antibiotics, making them less effective. 
- Novel BLIs that do not have the beta-lactam ring are thus necessary to find. 

Issues with current BLIs

Powers, R. A., Swanson, H. C., Taracila, M. A., Florek, N. W., Romagnoli, C., Caselli, E., Prati, F., Bonomo, R. A., & Wallar, B. J. (2014). Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumannii. Biochemistry, 53(48), 7670–7679. https://doi.org/10.1021/bi500887n

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