Site-Specific Antimicrobial Activity of a Dual-Responsive Ciprofloxacin Prodrug.
J Med Chem
; 67(11): 9599-9612, 2024 Jun 13.
Article
en En
| MEDLINE
| ID: mdl-38780408
ABSTRACT
Bacterial infections create distinctive microenvironments with a unique mix of metabolites and enzymes compared with healthy tissues that can be used to trigger the activation of antibiotic prodrugs. Here, a single and dual prodrug masking the C3 carboxylate and C7 piperazine of the fluoroquinolone, ciprofloxacin, responsive to nitroreductase (NTR) and/or hydrogen sulfide (H2S), was developed. Masking both functional groups reduced the activity of the prodrug against Staphylococcus aureus and Escherichia coli, increasing its minimum inhibitory concentration (MIC) by â¼512-fold (S. aureus) and â¼8000-fold (E. coli strains), while masking a single group only increased the MIC by â¼128-fold. Bacteria subjected to prolonged prodrug exposure did not show any increase in resistance. Triggering assays demonstrated the conversion of prodrugs to ciprofloxacin, and in a murine infection model, responsive prodrugs showed antibacterial activity comparable to that of ciprofloxacin, suggesting in vivo activation of prodrugs. Thus, the potential for site-specific antibiotic treatment with reduced threat of resistance is demonstrated.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Staphylococcus aureus
/
Profármacos
/
Ciprofloxacina
/
Pruebas de Sensibilidad Microbiana
/
Escherichia coli
/
Antibacterianos
Límite:
Animals
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Nueva Zelanda