Insights into the Mechanism of Fengycin, an Antimicrobial Lipopeptide using Multiscale Simulations

Abstract

Fengycin is a class of antimicrobial fungicide, synthesized by the bacterial family, Bacillus, which functions by damaging the fungus’ cell membrane. Thus it is cumbersome for the bacteria to develop resistance against it. This makes fengycin a potential drug candidate and comprehending its mechanism of action is a crucial step in drug development. Previously, it has been observed in coarse-grained simulations that fengycins form clusters in model fungal membranes (POPC) but not in model bacterial membranes (POPE:POPG). Our hypothesis is that formation of clusters plays a crucial step for fengycin disrupting the fungal membranes. However, most recent all-atom simulations results suggest that preference for the aggregation process in one membrane over the other is not statistically significant, although this may be more due to slow convergence than a true lack of selectivity. Accordingly, we are using enhanced sampling techniques are being used to compute the free energy change during aggregation in the two membrane types. In addition, it is important to study the effects of sterols on fengycin action, since one of the major differences between mammalian and fungal membranes is the presence of cholesterol versus ergosterol in the outer membrane. Therefore, coarse-grained simulations of lipids with cholesterol will show how these sterols can inhibit or promote the action of fengycin. These results will lead us to a more coherent understanding of the function of this unique biological molecule.