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


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
Issue number20
StatePublished - Oct 27 2022

Bibliographical note

Funding Information:
This work was supported by RO1 AI146116 and R21 AI130540. The following reagent S. aureus strain FPR3757 was provided by the Network on Antimicrobial Resistance in S. aureus (NARSA) for distribution by BEI Resources, NIAID, NIH: Nebraska Transposon Mutant Library (NTML) Genetic Toolbox, NR-48850. This study was also funded by a La Caixa Junior Leader Fellowship (LCF/BQ/PI20/11760012) financed by “la Caixa” Foundation (ID 100010434) and by European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no 847648 (P.M.P.), by the European Research Council through grant ERC-2017-CoG-771709 (M.G.P.), and by Project LISBOA-01-0145-FEDER-007660 Microbiologia Molecular, Estrutural e Celular (ITQB-NOVA).

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© 2022 American Chemical Society. All rights reserved.

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