The widespread use of antibacterial agents has had a dramatic beneficial effect on human health in the last century. However, since pathogens are increasingly resistant to current antibacterial agents, new antibacterials are urgently needed.  Antibacterials that have mechanisms of action that may be less likely to incur rapid resistance are especially desirable.1 The development of new antimicrobial dendrimers that are expected to have properties that make it difficult for bacteria to develop resistance to them is the focus of this project.

We recently initiated a collaboration with Dr. Robert Engel (Queens College, City University of New York). A major focus of effort in Dr. Robert Engel’s research program is the binding of quaternary ammonium salts with attached alkyl chains to surfaces to give the surfaces antimicrobial properties.  The cationic surfactants are believed to bind to anionic cell walls, disrupting the membrane and permitting the release of electrolytes and nucleic materials, which leads to cell death.2

We synthesized DABCO (1,4-diazabicyclo[2.2.2]octane) functionalized glycodendrimer 1 in which each dendrimer bears many DABCO units. DABCO-appended glycodendrimers are nanomaterials that are soluble in aqueous solutions and bear a large amount of positive charge. These new compounds also have a hexadecyl carbon chain to facilitate their interaction with the bacterial cell membrane. Unlike typical antibiotics that target genetic functions of a microorganism, the DABCO functionalized glycodendrimer is a highly cationic system that provides a mechanism for complete cell disruption.  It is highly unlikely that microorganisms could adapt and develop resistance to large, highly cationic dendrimers.

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Bacterial toxicity assays, biofilm inhibition studies, and hemolysis and cytotoxicity studies with mammalian cells are ongoing with 1 in the lab.

References

  1. MacDougall, C.; Polk, R. E., Antimicrobial stewardship programs in health care systems. Clinical Microbiology Reviews 2005, 18 (4), 638.
  2. Abel, T.; Cohen, J. I.; Engel, R.; Filshtinskaya, M.; Melkonian, A.; Melkonian, K., Preparation and investigation of antibacterial carbohydrate-based surfaces. Carbohydrate Research 2002, 337 (24), 2495-2499.