Synthesis, antimicrobial activity, attenuation of aminoglycoside resistance in MRSA, and ribosomal A-site binding of pyrene-neomycin conjugates.
Aminoglycosides
/ pharmacology
Animals
Binding Sites
Drug Resistance, Bacterial
/ drug effects
Framycetin
/ chemistry
Gram-Positive Bacteria
/ drug effects
Humans
Methicillin-Resistant Staphylococcus aureus
/ drug effects
Protein Binding
Pyrenes
/ chemistry
Ribosomal Proteins
Staphylococcal Infections
/ drug therapy
Aminoglycoside
MRSA
Neomycin
RNA
Ribosome
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
01 Feb 2019
01 Feb 2019
Historique:
received:
26
07
2018
revised:
07
11
2018
accepted:
08
11
2018
pubmed:
12
12
2018
medline:
12
2
2019
entrez:
12
12
2018
Statut:
ppublish
Résumé
The development of new ligands that have comparable or enhanced therapeutic efficacy relative to current drugs is vital to the health of the global community in the short and long term. One strategy to accomplish this goal is to functionalize sites on current antimicrobials to enhance specificity and affinity while abating resistance mechanisms of infectious organisms. Herein, we report the synthesis of a series of pyrene-neomycin B (PYR-NEO) conjugates, their binding affinity to A-site RNA targets, resistance to aminoglycoside-modifying enzymes (AMEs), and antibacterial activity against a wide variety of bacterial strains of clinical relevance. PYR-NEO conjugation significantly alters the affinities of NEO for bacterial A-site targets. The conjugation of PYR to NEO significantly increased the resistance of NEO to AME modification. PYR-NEO conjugates exhibited broad-spectrum activity towards Gram-positive bacteria, including improved activity against NEO-resistant methicillin-resistant Staphylococcus aureus (MRSA) strains.
Identifiants
pubmed: 30530174
pii: S0223-5234(18)30980-2
doi: 10.1016/j.ejmech.2018.11.022
pmc: PMC6503653
mid: NIHMS1516202
pii:
doi:
Substances chimiques
Aminoglycosides
0
Pyrenes
0
Ribosomal Proteins
0
Framycetin
4BOC774388
ribosomal protein L7-L12
70815-33-7
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
381-393Subventions
Organisme : NIAID NIH HHS
ID : R41 AI126874
Pays : United States
Organisme : NIGMS NIH HHS
ID : R42 GM097917
Pays : United States
Organisme : NIGMS NIH HHS
ID : R41 GM097917
Pays : United States
Organisme : NIDCD NIH HHS
ID : R41 DC016257
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI090048
Pays : United States
Informations de copyright
Copyright © 2018 Elsevier Masson SAS. All rights reserved.