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

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.

Synthesis of 20‐Membered Macrocyclic Pseudo‐Natural Products Yields Inducers of LC3 Lipidation

“…and Wang et al. ; [29] for details see below) were esterified with a Boc‐protected glycine and subsequently converted into aldehydes 3 and 12 a – g by means of Sharpless dihydroxylation followed by diol oxidation with NaIO 4 (Scheme 2). [30] …”

“… [28] C6′ ether derivatives were generated from quinidine via boron tribromide mediated demethylation followed by an alkylation with alkyl halides ( 10 a and 10 b , Scheme 2). [29] Maleimides 5 ad – bb were synthesized from the respective enantiopure primary amines and maleic anhydride (Supporting Information) [33] …”

Instructive Advances in Chemical Microbiology Inspired by Nature’s Diverse Inventory of Molecules

“…The pneumococcal vaccine PCV13 provides immunity to 13 of the most prevalent S. pneumoniae serotypes and has significantly reduced pneumococcal disease worldwide. However, widespread use of PCV13 and the vaccine PCV7 has led to increased incidences of drug-resistant S. pneumoniae infections, complicating therapy for those unvaccinated or infected with one of the 80 serotypes not covered by these vaccines …”

A Review of Modifications of Quinoline Antimalarials: Mefloquine and (hydroxy)Chloroquine

“…Sometimes it is a single-step process [ 6 , 7 ]. In the case of Cinchona alkaloids, this approach has been used to make analogs that are effective chiral catalysts or show promising antibiotic properties [ 8 , 9 , 10 ]. Unlike the natural products [ 8 , 9 ] or the de novo synthesized analogs [ 11 , 12 , 13 , 14 ], there is no comprehensive review on the late-stage modification of other quinoline drugs.…”