Principal Investigators:
Peter Elsbach, M.D. and Jerrold Weiss, Ph.D.
Departments of Medicine and Microbiology, New York University School of Medicine.

Background:
With the increase in resistance of bacteria to antibiotic treatment, attention has focussed on developing novel means of anti-microbial therapies. One approach is to exploit natural mechanisms used by mammals including humans to combat microbial invaders. Host responses to infection include extracellular mobilization of Group II phospholipase A2 (PLA2). This enzyme is a member of a conserved family of 14 kD PLA2 found in a wide range of sources from mammals, to insects and snakes. These phospholipases have highly conserved structural features required for Ca2+-dependent hydrolysis of phospholipid substrates but also highly variable surface regions mediating targeting of the enzyme to specific biological targets. The functional consequences of increased extracellular Group II PLA2 in inflammation are largely unknown. However, work in this laboratory has established that this enzyme, in concert with other host defense systems, can promote destruction of Gram-negative bacteria. This activity depends on specific structural characteristics of a discrete variable surface region that is not shared by most other members of this enzyme family.

Description of the Project:
Drs. Elsbach and Weiss have discovered a new antibacterial activity of mammalian (e.g. human) Group II PLA2. In local inflammatory (ascitic) fluid of rabbits and in sera of baboons collected during systemic inflammation, increased PLA2 levels are associated with potent bactericidal activity, not present in normal body fluids, against Staphylococcus aureus (including antibiotic resistant strains) and other Gram-positive bacteria. This activity is completely blocked by antibody specific to Group II PLA2. The PLA2 alone can kill Gram-positive bacteria but its potency is further enhanced by factor(s) present constitutively in plasma. This activity is dependent on the catalytic properties of the enzyme. However, several other closely related 14 kD PLA2 with closely similar catalytic properties display no antibacterial activity, indicating that the bactericidal properties of mammalian Group II PLA2 also depend on properties of the enzyme outside of the conserved catalytic site. It has been speculated that high levels of Group II PLA2 in body fluids contribute to pathologic alterations of host cells during inflammation. However, these novel findings demonstrate potent activity against bacteria at much lower enzyme concentrations and suggest possible therapeutic applications toward invasive infections by staphylococci, streptococci and other Gram-positive bacteria when endogenous mobilization of Group II PLA2 may be limiting.

Applications:
NYU is seeking a) a research collaboration to investigate the mechanism of action and, b) to license this novel technology.

Patent Status:
A provisional patent application has been filed in the United States.

For further information please contact:
New York University
Industrial Liaison/Technology Transfer
650 First Avenue, New York, N.Y. 10016
Tel: (212)263-8178 Fax: (212)263-8189