- 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

- The search for beta-lactamase inhibitors (BLIs) is critical in combating antibiotic resistance. 
- They halt the mechanism of beta-lactamases by chemically mimicking the beta-lactam ring to bind to the enzyme but it stops the catalytic activity of the enzyme. 
- Most have contained the beta-lactam ring as well.
- Clavulanic acid is an example (image below)

Grand Valley State University

Bacteria achieve resistance to beta-lactam antibiotics primarily through the production of beta-lactamase enzymes. These enzymes bind to the antibiotic's characteristic beta-lactam ring and hydrolyze it, breaking the ring structure. This inactivation prevents the antibiotic from inhibiting cell wall synthesis, rendering it ineffective.

Mechanism of Beta-Lactam Resistance

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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