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

Optochin, a cinchona alkaloid derivative discovered over 100 years ago, possesses highly selective antibacterial activity towards 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 48 likely binds to the c-ring of ATP synthase near the conserved glutamate 52 ion binding site while mechanistic studies demonstrated 48 causes cytoplasmic acidification. Initial pharmacokinetic and drug metabolism analysis of optochin and 48 revealed limitations of these quinine analogues, which were rapidly cleared resulting in poor in vivo exposure through hydroxylation pendant to the quinuclidine and O-dealklyation of the quinoline. Collectively, the results provide a foundation to advance 48 and highlight ATP synthase as a promising target for antibiotic development.