Synthesis, Stereochemical
Resolution, and Analogue
Synthesis of Variabiline, an Aporphine Alkaloid That Sensitizes Acinetobacter baumannii and Klebsiella pneumoniae to Colistin
posted on 2024-03-16, 15:19authored byHaoting Li, Ansley M. Nemeth, Roberta J. Melander, Christian Melander
Increasing antimicrobial resistance, coupled with the
absence of
new antibiotics, has led physicians to rely on colistin, a polymyxin
with known nephrotoxicity, as the antibiotic of last resort for the
treatment of infections caused by Gram-negative bacteria. One approach
to increasing antibiotic efficacy and thereby reducing dosage is the
use of small-molecule potentiators that augment antibiotic activity.
We recently identified the aporphine alkaloid (±)-variabiline,
which lowers the minimum inhibitory concentration of colistin in Acinetobacter baumannii and Klebsiella pneumoniae. Herein, we report the first total synthesis of (±)-variabiline
to confirm structure and activity, the resolution, and evaluation
of both enantiomers as colistin potentiators, and a structure–activity
relationship study that identifies more potent variabiline derivatives.
Preliminary mechanistic studies indicate that (±)-variabiline
and its derivatives potentiate colistin by targeting the Gram-negative
outer membrane.