1. Academic Validation
  2. A Cinchona Alkaloid Antibiotic That Appears To Target ATP Synthase in Streptococcus pneumoniae

A Cinchona Alkaloid Antibiotic That Appears To Target ATP Synthase in Streptococcus pneumoniae

  • J Med Chem. 2019 Mar 14;62(5):2305-2332. doi: 10.1021/acs.jmedchem.8b01353.
Xu Wang Yuna Zeng 1 Li Sheng Peter Larson 2 Xue Liu 1 Xiaowen Zou Shufang Wang Kaijing Guo Chen Ma Gang Zhang Huaqing Cui David M Ferguson 2 Yan Li Jingren Zhang 1 Courtney C Aldrich 2
Affiliations

Affiliations

  • 1 Center for Infectious Disease Research, School of Medicine , Tsinghua University , Beijing 100084 , People's Republic of China.
  • 2 Department of Medicinal Chemistry , University of Minnesota , Minneapolis , Minnesota 55455 , United States.
Abstract

Optochin, a cinchona alkaloid derivative discovered over 100 years ago, possesses highly selective Antibacterial activity toward Streptococcus pneumoniae. Pneumococcal disease remains the leading source of Bacterial pneumonia and meningitis worldwide. The structure-activity relationships of optochin were examined through modification to both the quinoline and quinuclidine subunits, which led to the identification of analogue 48 with substantially improved activity. Resistance and molecular modeling studies indicate that 48 likely binds to the c-ring of ATP Synthase near the conserved glutamate 52 ion-binding site, while mechanistic studies demonstrated that 48 causes cytoplasmic acidification. Initial pharmacokinetic and drug metabolism analyses of optochin and 48 revealed limitations of these quinine analogues, which were rapidly cleared, resulting in poor in vivo exposure through hydroxylation pendants to the quinuclidine and O-dealkylation of the quinoline. Collectively, the results provide a foundation to advance 48 and highlight ATP Synthase as a promising target for Antibiotic development.

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