Design,Synthesis And Antibacterial Evaluation Of Siderophore-based "Trojan Horse" Conjugates

Treating drug-resistant bacterial infections is always a challenge and an active research field.Scientists have developed various methods to overcome bacterial resistance for decades.The siderophore delivery strategy can help not only to enhance the intracellular concentration of antibiotics leading to improved antibacterial activity,but also overcome the drug resistance caused by reduced cell wall permeability.The first part of this thesis is on the design,synthesis and antibacterial studies of siderophore-Michael acceptor conjugates.The siderophore ultilized is Ferrichrome analogue as in natural Albomycin,which was conjugated with electrophilic "warhead"(Michael acceptor).It was expected that the electrophilic "warhead" could react with the lysine in the Ferrichrome transporter to form an irrevesible conjugate via Michaeladdition reaction,which would prevent iron-siderophore complex from binding to the transporter,thus resulting in insufficient iron transportation and lack of nutrient in bacteria.We optimized the synthesis of siderophore and coupled it with four types of Michael acceptors through ethylenediamine linker.In vitro antibacterial studies suggested that these compounds had no inhibitory activity against Escherichia coli,Staphylococcus aureus,Yersinia enterocolitica and Streptococcus pneumoniae.It was speculated that blocking one pathway might not be sufficient to inhibit iron uptake,or that the covalent crosslinking did not take place effectively.The second part is on the design,synthesis and antibacterial studies of siderophoreciprofloxacin conjugates 3-8 and 3-9.The siderophore was designed to deliver the ciprofloxacin into the bacteria,and the disulfide bond would break in the presence of the reductive substance such as GSH,which would release ciprofloxacin,in hope to improve ciprofloxacin’s efficacy.In vitro antibacterial activity studies revealed that compound 3-8 only showed MIC of 4 μg/m L against E.coli ATCC 25922(MIC of ciprofloxacin is below 0.125 μg/m L).Compound 3-9 exhibited poor antibacterial effects against seven tested strains.It’s plausible that the disulfide linker was not broken inside bacteria,preventing the release of ciprofloxacin,thus resulting in reduced efficacy.