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

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

  • J Med Chem. 2022 Oct 27;65(20):13910-13934. doi: 10.1021/acs.jmedchem.2c01151.
John R Schultz 1,  Stephen K Costa 2,  Gorakhnath R Jachak 1,  Pooja Hegde 1,  Matthew Zimmerman 3,  Yan Pan 3,  Michaele Josten 4,  Chinedu Ejeh 2,  Travis Hammerstad 1,  Hans Georg Sahl 4,  Pedro M Pereira 5,  Mariana G Pinho 5,  Véronique Dartois 3,  Ambrose Cheung 2,  Courtney C Aldrich 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
  • 2 Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, United States.
  • 3 Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey 07110, United States.
  • 4 Institute for Pharmaceutical Microbiology and Institute for Medical Microbiology, Immunology, and Parasitology, University of Bonn, D-53115 Bonn, Germany.
  • 5 Bacterial Cell Biology Laboratory, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Avenida da República (EAN), 2781-901 Oeiras, Portugal.
PMID: 36219779 DOI: 10.1021/acs.jmedchem.2c01151
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.

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