The fungal plasma membrane H+-ATPase as an ideal antifungal target
Currently, an estimated 40% of world food and feed production is lost annually due to fungal infections. Ongoing climate changes towards a warmer and more humid environment are expected to cause an increase in the frequency and amplitude of such fungal infections. Novel green technology aims at refining natural defence mechanisms for protection against fungi.
The fungal plasma membrane (PM) H+-ATPase is an ideal antifungal target as it is an essential enzyme not found in animals and an important functional part of the protein is exposed to the cell exterior.
We propose that many natural plant products have this proton pump as a target and that effective pump inhibitors should be sought for in plant extracts by screening for their effect on H+-ATPase activity.
Structures of the H+-ATPase co-crystallized with identified inhibitors will provide information on inhibitor binding pockets in the pump and offer a crucial rationale for the development of novel efficient and specific antifungals.
This project (FungalFight) involves collaboration partners at Department of Plant and Environmental Sciences, University of Copenhagen (prof. Michael Palmgren; coordinator), Department of Molecular Biology and Genetics, Aarhus University (prof. Poul Nissen), Department of Drug Design and Pharmacology, University of Copenhagen (prof. Søren Brøgger Christensen), and the start-up company Pcovery Aps (Dr. Anne-Marie L. Winther). FungalFight is supported by a grant from the Danish Council for Strategic Research (2011-2014).
Pcovery has recently received strong support from the Welcome Trust foundation: Press release
Yatime L, Buch-Pedersen MJ, Musgaard M, Morth JP, Lund Winther AM, Pedersen BP, Olesen C, Andersen JP, Vilsen B, Schiøtt B, Palmgren MG, Møller JV, Nissen P, Fedosova N (2009) P-type ATPases as drug targets: tools for medicine and science. Biochim Biophys Acta. 1787: 207-20.