Multivalent Glycopolymer Design Unlocks Antimicrobial Activity of 2‐Deoxyglucose

ABSTRACT With the increasing prevalence of multidrug‐resistant (MDR) pathogens, last‐line therapeutics such as cyclic peptides are insufficient, underscoring the need for new classes of antimicrobial compounds with distinct mechanisms of action. Here, we report a novel approach to glycan‐derived antimicrobials that transforms 2‐deoxyglucose (2DG), benign small molecules, into a potent antibiotic through its multivalent display as a glycopolymer. Toward this end, we synthesized a 2DG derivative amenable to ring opening metathesis polymerization (ROMP) and evaluated the impact of both spacing between 2DG and polymer backbone, as well as degree of polymerization. Shorter linkers and lower degrees of polymerization yielded the most potent antimicrobial polymer, hereafter referred to as poly2DG. Significantly, poly2DG exhibits broad‐spectrum bacterial inhibition, including against MDR methicillin‐resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa , and Acinetobacter baumannii , with MIC 50 values as low as 0.2 µg/mL. No such effect is observed for “free” 2DG nor the polymer scaffold alone, underscoring the importance of multivalent presentation for 2DG antibiotic activity. Altogether, this work shows the ability to convert an inert small molecule into an antimicrobial agent by simple polymeric scaffolding is a straightforward and effective chemical approach to develop materials that circumvent MDR.