4.7 Article

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

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JOURNAL OF MEDICINAL CHEMISTRY
卷 -, 期 -, 页码 -

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AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01151

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资金

  1. La Caixa Junior Leader Fellowship - la Caixa Foundation [LCF/BQ/PI20/11760012, 100010434]
  2. European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant [847648]
  3. European Research Council [ERC-2017-CoG-771709]
  4. [RO1 AI146116]
  5. [R21 AI130540]
  6. [LISBOA-01-0145-FEDER-007660]

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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.
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.

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