Inhibition of ß-lactamase function by de novo designed peptide.
PLoS One
; 18(9): e0290845, 2023.
Article
en En
| MEDLINE
| ID: mdl-37682912
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 ß-lactamase enzymes, overexpression of efflux pumps, reduced cell permeability through downregulation of porins required for ß-lactam entry, or modifications in penicillin-binding proteins. Inactivation of the ß-lactam antibiotics by ß-lactamase enzymes is the most common mechanism of bacterial resistance to these agents. Although several effective small-molecule inhibitors of ß-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-ß-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 ß-lactamase proteins and designed 30-mer peptides with the desired RRM spectral periodicities (frequencies) to function as ß-lactamase inhibitors. In contrast to the controls, our results indicate 100% inhibition of the class A ß-lactamases from Escherichia coli and Enterobacter cloacae. Taken together, the RRM model can likely be utilized as a promising approach to design ß-lactamase inhibitors for any specific class. This may open a new direction to combat antimicrobial resistance.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Beta-Lactamasas
/
Inhibidores de beta-Lactamasas
Idioma:
En
Revista:
PLoS One
Asunto de la revista:
CIENCIA
/
MEDICINA
Año:
2023
Tipo del documento:
Article
Pais de publicación:
Estados Unidos