N-Acetyl-D-Glucosamine Acts as Adjuvant that Re-Sensitizes Starvation-Induced Antibiotic-Tolerant Population of E. Coli to β-Lactam

Bacterial tolerance to antibiotics causes reduction in efficacy in antimicrobial treatment of chronic and recurrent infections. Nutrient availability is one major factor that determines the degree of phenotypic antibiotic tolerance. In an attempt to test if specific nutrients can reverse phenotypic tolerance, we identified N-acetyl-D-glucosamine (GlcNAc) as a potent tolerance-suppressing agent and showed that it could strongly re-sensitize a tolerant population of E. coli to ampicillin. Such re-sensitization effect was attributable to two physiology-modulating effects of GlcNAc. First, uptake of GlcNAc by the tolerant population triggers formation of the peptidoglycan precursor UDP-N-acetyl-D-glucosamine (UDP-GlcNAc) and subsequently re-activates the peptidoglycan biosynthesis process, rendering the organism susceptible to β-lactam antibiotics. Second, activation of glycolysis by-products of GlcNAc catabolism drives the re-sensitization process. Our findings imply that GlcNAc may serve as a non-toxic β-lactam adjuvant that enhances the efficacy of treatment of otherwise hard-to-treat bacterial infections due to phenotypic antibiotic tolerance.