Novel Developments For Increased Efficacy And Longevity Of Existing Clinically Approved Antibiotics

Ciprofloxacin is a fluoroquinolone, broad spectrum antibacterial agent where it fights against both Gram positive and Gram negative bacteria. It usually enters the bacteria via porins such as OmpF in E. coli and binds with the DNA proteins called DNA gyrase or DNA topoisomerase IV and a bacterial DNA to form a ternary complex in the cytoplasm. Mutation in the regulatory gene of bacterial DNA affects the biological synthesis of porins where it reduces the porins, and this usually associates with overproduction of efflux pumps, which lead to low concentration of ciprofloxacin in the bacteria. Therefore, it does not reach to the fatal level and the bacteria are still able to survive even though they are exposed to antibiotics. This condition is called antibiotic resistance. ‘Trojan Horse’ strategy is one of the strategies to solve this phenomenon, where the antibiotic is smuggled into the cytoplasm of the bacteria by a vector called siderophore, which in nature, it is secreted by the bacteria to solubilise the ferric iron and enter the bacteria through the active pump for their survival. Our research group has synthesised many new siderophore-drug conjugates that based on the fluoroquinolone as the drug and δ-hydroxycarboxylate-type of siderophore as a vector. In this project, different polarities of 1,5-citrate ciprofloxacin conjugates were successfully synthesised and screened with a panel of clinically relevant bacteria and found that the using 1,5-citrate as a siderophore and hydrophilicity of siderophore-drug conjugates can improve marginally the efficacy of the drug conjugates.