Mode of action of membrane-targeting antimicrobial compounds

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Membrane-targeting antimicrobials (MTAs) have been employed successfully in medicine for a number of years. There are theoretical reasons why these antimicrobials might delay or even eliminate resistance development in sensitive pathogens. Yet surprisingly, use of MTAs against harmful plant and food microorganisms is still very limited. It is hypothesized that MTAs have a mode of action that is difficult for microorganisms to overcome and could therefore provide efficient and, most importantly, durable methods of control. The lack of fundamental knowledge on the mode of action of MTAs has most definitely hampered the efficient use of these types of antimicrobials. The long term goal of this research program aims to elucidate the precise mode of action of MTAs for successful application of these compounds toward the control of harmful plant and food microorganisms. The present research proposal uses novel approaches to investigate the mechanisms of action of a specific MTA class (lipopeptides) at the molecular, cellular, and biochemical level. More precisely, the role of MTAs in increased membrane fluidity, membrane pore formation, and binding/interacting with membrane components will be studied through techniques such as total internal reflection fluorescence (TIRFM), atomic force (AFM) and electron (EM) microscopy, concurrently with techniques in bio-analytical and biophysical chemistry as well as biochemistry. This program will therefore shed light into the precise mode of action of these membrane-targeting compounds and provide insight into their development as novel, efficient, and long-lasting alternatives to synthetic chemicals against harmful plant and food microorganisms.