Rapid Intrabacterial Hydrolysis for Activating Antibiotics against Gram-negative Bacteria

Abstract

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. Further studies reveal that CLsuGG undergoes rapid hydrolysis catalyzed by intrabacterial esterases (e.g., BioH and YjfP) for generating chloramphenicol (CL) in E. coli. More importantly, the conjugate exhibits lower cytotoxicity to bone marrow stromal cells that CL does. The structural analogs of CLsuGG indicate that the conjugation of GG is an effective strategy for accelerating hydrolysis catalyzed by esterases and enhancing antibacterial efficacy of antibiotics. This work, for the first time, illustrates that dipeptide conjugation modulates intrabacterial hydrolysis for increasing antibiotic efficacy and reducing adverse drug effects.Infectious disease remains a major threat to public health.