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.
Keywords: adjuvant; antibiotic resistance; colistin; structure−activity relationship; total synthesis.