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

• Published in: Journal of medicinal chemistry Vol. 65; no. 20; pp. 13910 - 13934
• Main Authors: Schultz, John R., Costa, Stephen K., Jachak, Gorakhnath R., Hegde, Pooja, Zimmerman, Matthew, Pan, Yan, Josten, Michaele, Ejeh, Chinedu, Hammerstad, Travis, Sahl, Hans Georg, Pereira, Pedro M., Pinho, Mariana G., Dartois, Véronique, Cheung, Ambrose, Aldrich, Courtney C.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.10.2022; Amer Chemical Soc
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Chemistry, Medicinal; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Pharmacology & Pharmacy; Quinolones - pharmacology; Science & Technology; METHICILLIN-RESISTANT; BETA-LACTAM RESISTANCE; QUINOLINE; SMALL-MOLECULE; CARE-ASSOCIATED INFECTIONS; STAPHYLOCOCCUS-AUREUS; HEALTH-CARE; PROTEINS; DERIVATIVES; EMERGENCE
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01151

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.