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

Nosocomial infections caused by resistant Grampositive 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-4quinolone 111 with exceptionally potent Gram-positive activity with minimum inhibitory concentrations (MICs) <= 0.06 mu g/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.

Automated summary

Nosocomial infections caused by resistant Gram-positive organisms are increasing, and new drugs are urgently needed. This study describes the identification of a 5-amino-4-quinolone with potent Gram-positive activity and preliminary understanding of its mechanism of action and resistance. The compound shows promising antibacterial properties and warrants further investigation for the treatment of Gram-positive infections.