: Combined therapy with penicillins and aminoglycosides has been proved beneficial to address many persistent bacterial infections with possible synergistic effects. However, the different pharmacokinetic profiles of these two antibiotic classes may not guarantee a concerted spatio-temporal delivery at the site of action, decreasing the efficacy of this combination and promoting resistance. Herein, we propose a multifunctional antibiotic-polymer conjugate, designed to colocalize ampicillin and gentamicin to tackle persistent biofilm infections. The two antibacterial molecules were grafted along with the amino acid l-arginine to a biocompatible polymer backbone with peptidomimetic hydrophilic structure, obtaining the antimicrobial poly(argilylaspartamide-co-aspartic) acid-ampicillin, gentamicin (PAA-AG) conjugate. The PAA-AG conjugate displayed excellent biocompatibility on human cell lines if compared with free drugs, potentially enlarging their therapeutic window and safety, and suitable mucoadhesive characteristics which may help local treatments of mucosal infections. Studies on planktonic cultures of clinical and reference strains of S. aureus, P. aeruginosa, and E. coli revealed that PAA-AG holds a broad-spectrum antibacterial efficacy, revealing high potency in inhibiting the growth of the tested strains. More interestingly, PAA-AG exhibited excellent antibiofilm activity on both Gram+ and Gram- communities, showing inhibition of their formation at subMIC concentrations as well as inducing the regression of mature biofilms. Given the high biocompatibility and broad antibiofilm efficacy, combined with the opportunity for synchronous co-delivery, the PAA-AG conjugate could be a valuable tool to increase the success of ampicillin/gentamicin-based antibiotic multitherapy.

Varvarà, P., Calà, C., Maida, C.M., Giuffrè, M., Mauro, N., Cavallaro, G. (2023). Arginine-Rich Peptidomimetic Ampicillin/Gentamicin Conjugate To Tackle Nosocomial Biofilms: A Promising Strategy To Repurpose First-Line Antibiotics. ACS INFECTIOUS DISEASES, 9(4), 916-927 [10.1021/acsinfecdis.2c00579].

Arginine-Rich Peptidomimetic Ampicillin/Gentamicin Conjugate To Tackle Nosocomial Biofilms: A Promising Strategy To Repurpose First-Line Antibiotics

Calà, Cinzia
Secondo
Data Curation
;
Maida, Carmelo M
Writing – Original Draft Preparation
;
Giuffrè, Mario
Writing – Review & Editing
;
Mauro, Nicolò
Penultimo
Conceptualization
;
Cavallaro, Gennara
Ultimo
Funding Acquisition
2023-04-14

Abstract

: Combined therapy with penicillins and aminoglycosides has been proved beneficial to address many persistent bacterial infections with possible synergistic effects. However, the different pharmacokinetic profiles of these two antibiotic classes may not guarantee a concerted spatio-temporal delivery at the site of action, decreasing the efficacy of this combination and promoting resistance. Herein, we propose a multifunctional antibiotic-polymer conjugate, designed to colocalize ampicillin and gentamicin to tackle persistent biofilm infections. The two antibacterial molecules were grafted along with the amino acid l-arginine to a biocompatible polymer backbone with peptidomimetic hydrophilic structure, obtaining the antimicrobial poly(argilylaspartamide-co-aspartic) acid-ampicillin, gentamicin (PAA-AG) conjugate. The PAA-AG conjugate displayed excellent biocompatibility on human cell lines if compared with free drugs, potentially enlarging their therapeutic window and safety, and suitable mucoadhesive characteristics which may help local treatments of mucosal infections. Studies on planktonic cultures of clinical and reference strains of S. aureus, P. aeruginosa, and E. coli revealed that PAA-AG holds a broad-spectrum antibacterial efficacy, revealing high potency in inhibiting the growth of the tested strains. More interestingly, PAA-AG exhibited excellent antibiofilm activity on both Gram+ and Gram- communities, showing inhibition of their formation at subMIC concentrations as well as inducing the regression of mature biofilms. Given the high biocompatibility and broad antibiofilm efficacy, combined with the opportunity for synchronous co-delivery, the PAA-AG conjugate could be a valuable tool to increase the success of ampicillin/gentamicin-based antibiotic multitherapy.
14-apr-2023
Settore CHIM/09 - Farmaceutico Tecnologico Applicativo
Settore MED/42 - Igiene Generale E Applicata
Varvarà, P., Calà, C., Maida, C.M., Giuffrè, M., Mauro, N., Cavallaro, G. (2023). Arginine-Rich Peptidomimetic Ampicillin/Gentamicin Conjugate To Tackle Nosocomial Biofilms: A Promising Strategy To Repurpose First-Line Antibiotics. ACS INFECTIOUS DISEASES, 9(4), 916-927 [10.1021/acsinfecdis.2c00579].
File in questo prodotto:
File Dimensione Formato  
acsinfecdis.2c00579_compressed.pdf

Solo gestori archvio

Descrizione: Articolo
Tipologia: Versione Editoriale
Dimensione 1.32 MB
Formato Adobe PDF
1.32 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/588632
Citazioni
  • ???jsp.display-item.citation.pmc??? 1
  • Scopus 1
  • ???jsp.display-item.citation.isi??? 1
social impact