The increasing emergence of multiple drug-resistant microorganisms has provided additional efforts to elucidate molecular descriptions of membrane-related processes. The need of cell specific drug delivery and ongoing progress in the molecular description of neurodegenerative diseases underline the significance of these aims. Inspired by the mode of action of endogenous antibiotics, the PI intends to devise fundamentally new classes of cell membrane specific antimicrobial agents which are hoped to cause rare development of resistance. The rationally designed synthetic target molecules are non-peptide amphiphilic rigid-rod molecules which represent, to the best knowledge of the PI, a new class of compounds. Specific, voltage-gated ion channel formation within cell membranes having the unusually negative membrane potentials of pathogens will be attempted by increasing the overall electric dipole moment of pore forming rigid-rod molecules. The synthesis of amphiphilic rigid-rod molecules which carry terminal polyamine dendrimers will permit the evaluation of an alternative, new approach towards voltage-gated channel formation via induced local micellization. Long rigid-rod molecules (greater than 40 Angstroms) should bind only to """"""""thick"""""""" membranes. Specific pore formation within """"""""thick"""""""" membranes may open new routes towards the treatment of multiple drug-resistant mycobacteria (e.g. tubercle bacillus). It is aimed to extend the proposed concept towards biomimetic drug delivery systems using self-assembled rigid-rod molecules which carry specific receptor units along their membrane spanning skeleton. This may include specific transport of various biomolecules through polysteroidal or polyphenylenic pores, but may also include transport by rigid-rod-mediated endocytosis, membrane fusion, and via gap junctions between liposomes and cells. In the proposed case of rigid-rods which recognize """"""""thick"""""""" membranes, a long term goal is the biomimetic membrane specific transport of neurotransmitters or oligonucleotides through the blood-brain barrier. The methodological aims include the first direct detection of membrane curvature by the recently introduced porphyrin-reported exciton coupled circular dichroic method, which should lead to valuable assays capable of distinguishing between endo- and exocytosis. Furthermore, spectroscopic assays for the simultaneous detection of (supra)structure and activity of voltage-gated ion channels will be refined.
