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Inhibition of ß-lactamase function by de novo designed peptide.
Mishra, Arunima; Cosic, Irena; Loncarevic, Ivan; Cosic, Drasko; Fletcher, Hansel M.
Afiliación
  • Mishra A; Division of Microbiology & Molecular Genetics, School of Medicine, Loma Linda University, Loma Linda, California, United States America.
  • Cosic I; AMALNA Consulting, Black Rock, Melbourne, VIC, Australia.
  • Loncarevic I; QuantBioRes-QBR A/S, Copenhagen, Denmark.
  • Cosic D; AMALNA Consulting, Black Rock, Melbourne, VIC, Australia.
  • Fletcher HM; Division of Microbiology & Molecular Genetics, School of Medicine, Loma Linda University, Loma Linda, California, United States America.
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.
Asunto(s)

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

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