The main objective of this proposal is to understand the biological and biochemical basis of polyene antibiotic resistance and sensitivity. A genetic-physiological framework will be established for the study of polyene-resistant mutants and the analysis of polyene resistance and sensitivity through the study of these mutants. The framework will be constructed by isolating and genetically characterizing polyene-resistant mutants, analyzing the mutants for sterol alterations by gas chromatographic and mass spectroscopic analysis, screening the mutants for polyene-sterol binding and for the state of polyene- induced permeability. Although most of the evidence suggests that polyene caused cell death is the result of cell leakage, recent evidence suggests that the products of polyene autoxidation may be responsible for polyene toxicity. In his analysis of polyene-resistant mutants Dr. Katz has found a class of mutants that appear to be deficient in cell-substratum adhesion, reduced in membrane sterol content and increased in cellular peroxisomal activity. The relationship of these three results to each other and to polyene resistance and sensitivity will be further studied. Polyenes are widely used clinically important drugs whose mode of action depends on their interaction with membrane sterol. Sterols are major structural components of the plasma membrane whose function is largely unknown. There is a growing body of literature that indicates that they may play an active role in cellular regulation rather than only passively modulating membrane fluidity. Dictyostelium discoideum with its extensive developmental program which features such membrane processes as cell motility, adhesion and phagocytosis will be used for these studies.

Agency
National Science Foundation (NSF)
Institute
Division of Integrative Organismal Systems (IOS)
Application #
8703045
Program Officer
Kevin L. Thompson
Project Start
Project End
Budget Start
1987-07-15
Budget End
1991-06-30
Support Year
Fiscal Year
1987
Total Cost
$254,000
Indirect Cost
Name
State University New York Stony Brook
Department
Type
DUNS #
City
Stony Brook
State
NY
Country
United States
Zip Code
11794