Maxamycins: Durable Antibiotics Derived by Rational Redesign of Vancomycin

-(4-chlorobiphenyl)methyl (CBP) modification as well as newly discovered C-terminal trimethylammonium cation (C1) or guanidine modifications were introduced, providing two additional synergistic mechanisms of action independent of d-Ala-d-Ala/d-Lac binding. The CBP modification provides an additional stage for inhibition of cell wall synthesis that results from direct competitive inhibition of transglycosylase, whereas the C1/guanidine modification induces bacteria cell permeablization. The synergistic behavior of the three independent mechanisms of action combined in a single molecule provides ultrapotent antibiotics (MIC = 0.01-0.005 μg/mL against VanA VRE). Beyond the remarkable antimicrobial activity, the multiple mechanisms of action suppress the rate at which resistance may be selected, where any single mechanism of action is protected by the action of others. The results detailed herein show that rational targeting of durable vancomycin-derived antibiotics has generated compounds with a "resistance against resistance", provided new candidate antibiotics, and may serve as a generalizable strategy to combat antibacterial resistance.