Identification of 5-(Aryl/Heteroaryl)amino-4-quinolones as Potent Membrane-Disrupting Agents to Combat Antibiotic-Resistant Gram-Positive Bacteria

John Schultz, Stephen K. Costa, Gorakhnath R. Jachak, Pooja V Hegde, Matthew Zimmerman, Yan Pan, Michaele Josten, Chinedu Ejeh, Travis Hammerstad, Hans Georg Sahl, Pedro M. Pereira, Mariana G. Pinho, Véronique Dartois, Ambrose Cheung, Courtney C. Aldrich

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Nosocomial infections caused by resistant Gram-positive organisms are on the rise, presumably due to a combination of factors including prolonged hospital exposure, increased use of invasive procedures, and pervasive antibiotic therapy. Although antibiotic stewardship and infection control measures are helpful, newer agents against multidrug-resistant (MDR) Gram-positive bacteria are urgently needed. Here, we describe our efforts that led to the identification of 5-amino-4-quinolone 111 with exceptionally potent Gram-positive activity with minimum inhibitory concentrations (MICs) ≤0.06 μg/mL against numerous clinical isolates. Preliminary mechanism of action and resistance studies demonstrate that the 5-amino-4-quinolones are bacteriostatic, do not select for resistance, and selectively disrupt bacterial membranes. While the precise molecular mechanism has not been elucidated, the lead compound is nontoxic displaying a therapeutic index greater than 500, is devoid of hemolytic activity, and has attractive physicochemical properties (clog »P = 3.8, molecular weight (MW) = 441) that warrant further investigation of this promising antibacterial scaffold for the treatment of Gram-positive infections.

Original languageEnglish (US)
Pages (from-to)13910-13934
Number of pages25
JournalJournal of medicinal chemistry
Volume65
Issue number20
DOIs
StatePublished - Oct 27 2022

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