Inhibition of β-lactamase function by de novo designed peptide

Antimicrobial resistance is a great public health concern that is now described as a silent pandemic. The global burden of antimicrobial resistance requires new antibacterial treatments, especially for the most challenging multidrug-resistant bacteria. There are various mechanisms by which bacteria develop antimicrobial resistance including expression of beta-lactamase enzymes, overexpression of efflux pumps, reduced cell permeability through downregulation of porins required for beta-lactam entry, or modifications in penicillin-binding proteins. Inactivation of the beta-lactam antibiotics by beta-lactamase enzymes is the most common mechanism of bacterial resistance to these agents. Although several effective small-molecule inhibitors of beta-lactamases such as clavulanic acid and avibactam are clinically available, they act only on selected class A, C, and some class D enzymes. Currently, none of the clinically approved inhibitors can effectively inhibit Class B metallo-beta-lactamases. Additionally, there is increased resistance to these inhibitors reported in several bacteria. The objective of this study is to use the Resonant Recognition Model (RRM), as a novel strategy to inhibit/modulate specific antimicrobial resistance targets. The RRM is a bio-physical approach that analyzes the distribution of energies of free electrons and posits that there is a significant correlation between the spectra of this energy distribution and related protein biological activity. In this study, we have used the RRM concept to evaluate the structure-function properties of a group of 22 beta-lactamase proteins and designed 30-mer peptides with the desired RRM spectral periodicities (frequencies) to function as beta-lactamase inhibitors. In contrast to the controls, our results indicate 100% inhibition of the class A beta-lactamases from Escherichia coli and Enterobacter cloacae. Taken together, the RRM model can likely be utilized as a promising approach to design beta-lactamase inhibitors for any specific class. This may open a new direction to combat antimicrobial resistance.

Automated summary

Antimicrobial resistance is a global public health concern that requires new treatments, especially for multidrug-resistant bacteria. This study used the Resonant Recognition Model to evaluate the structure-function properties of beta-lactamase proteins and designed peptides as inhibitors, showing promising results.