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

Xu Wang, Yuna Zeng, Li Sheng, Peter Larson, Xue Liu, Xiaowen Zou, Shufang Wang, Kaijing Guo, Chen Ma, Gang Zhang, Huaqing Cui, David M Ferguson, Yan Li, Jingren Zhang, Courtney Aldrich

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2305-2332
Number of pages28
JournalJournal of Medicinal Chemistry
Volume62
Issue number5
DOIs
StatePublished - Mar 14 2019

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Cinchona Alkaloids
Quinuclidines
Streptococcus pneumoniae
Adenosine Triphosphate
Anti-Bacterial Agents
Dealkylation
Bacterial Pneumonia
Bacterial Meningitides
Quinine
Structure-Activity Relationship
Hydroxylation
Glutamic Acid
Pharmacokinetics
Binding Sites
Ions
Pharmaceutical Preparations
ethylhydrocupreine
quinoline

PubMed: MeSH publication types

  • Journal Article

Cite this

A Cinchona Alkaloid Antibiotic That Appears to Target ATP Synthase in Streptococcus pneumoniae. / Wang, Xu; Zeng, Yuna; Sheng, Li; Larson, Peter; Liu, Xue; Zou, Xiaowen; Wang, Shufang; Guo, Kaijing; Ma, Chen; Zhang, Gang; Cui, Huaqing; Ferguson, David M; Li, Yan; Zhang, Jingren; Aldrich, Courtney.

In: Journal of Medicinal Chemistry, Vol. 62, No. 5, 14.03.2019, p. 2305-2332.

Research output: Contribution to journalArticle

Wang, X, Zeng, Y, Sheng, L, Larson, P, Liu, X, Zou, X, Wang, S, Guo, K, Ma, C, Zhang, G, Cui, H, Ferguson, DM, Li, Y, Zhang, J & Aldrich, C 2019, 'A Cinchona Alkaloid Antibiotic That Appears to Target ATP Synthase in Streptococcus pneumoniae', Journal of Medicinal Chemistry, vol. 62, no. 5, pp. 2305-2332. https://doi.org/10.1021/acs.jmedchem.8b01353
Wang, Xu ; Zeng, Yuna ; Sheng, Li ; Larson, Peter ; Liu, Xue ; Zou, Xiaowen ; Wang, Shufang ; Guo, Kaijing ; Ma, Chen ; Zhang, Gang ; Cui, Huaqing ; Ferguson, David M ; Li, Yan ; Zhang, Jingren ; Aldrich, Courtney. / A Cinchona Alkaloid Antibiotic That Appears to Target ATP Synthase in Streptococcus pneumoniae. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 5. pp. 2305-2332.
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