Design and synthesis of cationic amphiphiles

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Date
2010, 2012, 2013, 2012
Authors
Findlay, Brandon
Journal Title
Journal ISSN
Volume Title
Publisher
American Society for Microbiology
Elsevier
Public Library of Science
Public Library of Science
Elsevier
Abstract
Cationic antimicrobial peptides (CAMPs) are produced by plants, animals and bacteria to protect their host against antagonistic microbes. The antitheses of selective antibiotics, these peptides are drawn by electrostatic and hydrophobic interactions to targets as diverse as the bacterial membrane, nucleic acids and serum proteins. This lack of specificity is their greatest strength, as mutations to single genes rarely lead to bacterial resistance. Resistance may be conferred by large scale alterations in cell envelope composition, which generally reduces bacterial fitness in the absence of peptide. Clinical applications of natural CAMPs are limited, as the peptides are toxic to mammalian cells and rapidly inactivated in vivo by serum albumin and proteases. Faced with these challenges we have prepared a number of CAMP analogues, with the goal of creating lead compounds for further development of antibacterial therapeutics. Much of our work has focused on ultrashort lipopeptides and lipopeptoids, which have properties similar to natural CAMPs and extremely abbreviated sequences. The simple structure of these scaffolds allows rapid creation of CAMP analogues in a brief period of time, allowing us to rapidly explore the structural requirements for CAMP activity. The balance of this work focuses on imparting CAMP-like behaviour to known antibiotics, in order to expand their spectrum of susceptible bacteria and combat the development of drug-resistant bacteria. In particular, the aminoglycosides neomycin and tobramycin have been fused to phenolic disinfectants such as triclosan and biclotymol, in order to improve their diffusion across the bacterial envelope and activity against Gram-negative bacteria.
Description
Keywords
cationic amphiphiles, lipopeptides, antibiotics, antimicrobial peptides, aminoglycosides, immunomodulatory peptides
Citation
Antimicrobial Agents and Chemotherapy, 54, 2010, 4049-58. doi: 10.1128/AAC.00530-10.
International Journal of Antimicrobial Agents, 40, 2012, 36-42. doi: 10.1016/j.ijantimicag.2012.03.013.
PLoS ONE, 2012, e41141. doi: 10.1371/journal.pone.0041141.
PLoS ONE, 2013, e54280. Doi: 10.1371/journal.pone.0054280.
Bioorganic Medicinal Chemistry Letters, 22, 2012, 1499-1503. doi: 10.1016/j.bmcl.2012.01.025.