Taming Antibiotics


Amphotericin B (AmpB) is a potent antifungal drug but is also highly toxic to
mammals. The specificity of its cell killing depends, significantly, on its monomer
vs. the aggregate state. Specifically, AmpB aggregates tend to rupture membranes
indiscriminately, like detergents, while the corresponding monomers sequester
ergosterol (a sterol found in fungal cells, but not mammalian cells) and disrupt
membrane structure and function. Current lipid-based formulations are less toxic
than “naked” AmpB because they prevent the formation of AmpB aggregates. While
effective, these lipid formulations are not perfect.

An inventor at Lehigh University has developed a strategy for reducing the toxicity of
aggregated forms of AmpB. This strategy involves the covalent attachment of
amphiphilic molecules that act as "floats", thereby reducing their ability to penetrate
deeply into the lipid membrane. As a consequence, membrane rupture events are
avoided. In a sense, these "floats" tame the antibiotic, thereby increasing its
selectivity. Specific examples of such tamed forms of AmpB, which retain their
antifungal activity but show dramaticallly reduced hemolytic activity are shown as
structures 1a, 1b, 1c, and 1d.



 Greater Selectivity and avoids the need for liposomal carriers

 Reduced toxicity

 Straightforward and molecular synthesis

 2 μM EC50 for killing of fungal cells, >400 μM EH50 for hemolysis, as
    compared with EH50 of 4 μM for AmB.

Lehigh University Tech ID #080115-01


Systemic fungal infections are particularly opportunistic in immune compromised
patients, affecting an estimated 400,000 patients globally. Lipid-based formulations
of amphotericin B have proven quite profitable, with AmpBisome® (developed by
Astellas & Gilead) generating revenue of $350 million in 2013, according to the
Gilead annual report.

Lehigh University is looking for a partner for further development and commercialization
of this technology. The inventor is available to collaborate with interested companies.

App Type Country Serial No. Patent No. File Date Issued Date Expire Date
Provisional [PR] United States 62/203,076 8/10/2015    
For Information, Contact:
Yatin Karpe
Associate Director
Lehigh University
Steven Regen