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.
|Number of pages||13|
|Journal||European Journal of Medicinal Chemistry|
|State||Published - Feb 1 2019|
Bibliographical noteFunding Information:
We thank the National Institute of Health for financial support (grants GM097917, AI111414 to D.P.A.) and (grant AI090048 to S.G.-T.).
We thank the National Institute of Health for financial support (grants GM097917 , AI111414 to D.P.A.) and (grant AI090048 to S.G.-T.).
© 2018 Elsevier Masson SAS
ASJC Scopus subject areas
- Drug Discovery
- Organic Chemistry