Synthesis of Vitamin B₁₂-Antibiotic Conjugates with Greatly Improved Activity against Gram-Negative Bacteria

There is an urgent need to discover new antibiotics and improve the efficacy of known antibiotics against Gram-negative bacteria. "Trojan horse" conjugates are novel and promising antibiotics. Herein we report the design and synthesis of vitamin-B₁₂-ampicillin conjugates, which exhibited more than 500 times improved activity against Escherichia coli compared with ampicillin itself. Our studies demonstrate that the vitamin-B₁₂ uptake pathway could be employed for effective antibiotic delivery and efficacy enhancement.