Host defense peptides; Peptidomimetics; Drug design; Drug resistance; Drug delivery.
The development of new, safe/efficient and economically viable tools for fighting multidrug resistant (MDR) pathogens is of prevalent need. The Mor group has recently reported a novel design of chemical mimics that is founded on lipopeptide-like oligomeric arrangements of acylated cationic building blocks. Initial characterization of lysine-based representatives (termed oligo-acyl-lysyls, OAKs) led to several intriguing findings: (i) The OAK platform can generate small molecules that selectively exert antimicrobial  (and anticancer ) properties using distinct sequence-specific mechanisms; (ii) Some OAKs can potentiate certain drugs (eg, antibiotics), restoring sensitivity of MDR cells, in some cases) ; (iii) OAKs interaction with phospholipids induce cochleates formation, which can be exploited for efficient co-encapsulation of the synergistic drugs and for co-delivery in systemic treatment of infection . Collectively, these findings argue for the potential of OAKs in providing a comprehensive system for fighting MDR bacteria .
The group’s current efforts attempt to extend these studies and exploit accumulated knowledge for further developing the OAK approach while focusing on particularly short antibacterial sequences. Thus, design principles that emerged from previous studies are used to inspire the design of new improved derivatives towards defining essential chemo-physical properties that impact extra- and intra-cellular targets, in presence and absence of antibiotics, in-vitro and in-vivo. Knowledge gained over the course of this project will aid in the rational design of optimal antimicrobial agents for mono- and/or combination-therapy.
 I. Radzishevsky, R.Shahar, D.Bourdetsky, S.Venezia, Y.Carmeli, A.Mor. Improved antimicrobial peptides based on acyl-lysine oligomers. Nature Biotechnology (2007) 25:657-9.
 Viki Held, Shahar Rotem, Yehuda Assaraf, Amram Mor. Mimics of Host-Defense Peptides as a Platform for Novel Anticancer Drugs FASEB J (2009) 23:4299-307.
 Liran Livne, Raquel Epand, Brigitte Sternberg, Richard Epand, Amram Mor. OAK-based cochleates as a novel approach to overcome multidrug resistance in bacteria. FASEB J. (2010) 24:5092-101.
 A.Mor. Chemical Mimics with Systemic Efficacy. In Antimicrobial Peptides: Discovery, Design and Novel Therapeutic Strategies, Wang, G., Ed.; CABI: Wallingford Oxfordshire, UK, 2010.