Abstract
Investigating the effect of lipid hydrophobicity on the activity of amphiphilic neomycin B conjugates, six polycationic amphiphiles (PAs) were created. Four of the new compounds incorporated either palmitic or arachidic di-lipid lysine tails, while two had single fluorinated undecanoic acid tails. The basicity of half of the compounds was increased through the incorporation of six guanidine moieties, in order to assess the effect of base strength on antimicrobial activity. A panel of ten bacteria was used for the testing, with seven strains obtained from the American Type Culture Collection series and three clinical isolates from Canadian Intensive Care Units. When compared to previous results with hydrocarbon monolipids the PAs all compounds were found to have reduced activity, though the hemolytic activity of the compounds with fluorinated tails was sharply reduced, with only a moderate reduction in antimicrobial activity.
Highlights
Much of our current antibiotic arsenal is derived from scaffolds developed forty or more years ago, allowing bacterial resistance to slowly accrue [1]
Starting from a class of compounds with known antibiotic action and limited ability to disrupt mammalian membranes, we have previously demonstrated the potential for a model aminoglycoside, neomycin, to act as a polycationic amphiphile (PA) [8,9,10,11,12]
The four step synthesis begins with protection of the amine functionalities, followed by conversion of the 5"-OH to a primary amine for standard amide bond formation (Scheme 1)
Summary
Much of our current antibiotic arsenal is derived from scaffolds developed forty or more years ago, allowing bacterial resistance to slowly accrue [1]. Polycationic lipids are one such scaffold, as agents such as chlorhexidine and benzalkonium chloride have been used as disinfectants for decades with little resistance development [3]. These compounds are toxic to mammalian cells, limiting their use to topical applications [3,4]. Starting from a class of compounds with known antibiotic action and limited ability to disrupt mammalian membranes, we have previously demonstrated the potential for a model aminoglycoside, neomycin, to act as a polycationic amphiphile (PA) [8,9,10,11,12]. In one study, coupling a single unit of palmitic acid to a C5"-amine restored good activity against a normally resistant strain of MRSA [12]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call