Rapid Intrabacterial Hydrolysis for Activating Antibiotics against Gram-negative Bacteria

Antimicrobial drug resistance demands novel approaches for improving the efficacy of antibiotics, especially against Gram-negative bacteria. Here we report that conjugating a diglycine (GG) to a prodrug of antibiotics drastically accelerates intrabacterial hydrolysis of ester bond for regenerating the antibiotics against E. coli. Specifically, the attachment of GG to chloramphenicol succinate (CLsu) generates a novel conjugate (CLsuGG), which exhibits about an order of magnitude higher inhibitory efficacy than CLsu against E. coli. This work, for the first time, illustrates that dipeptide conjugation modulates intrabacterial hydrolysis for increasing antibiotic efficacy and reducing adverse drug effects.