A54145 Factor D Is Not Less Susceptible to Inhibition by Lung Surfactant than Daptomycin

Abstract

A54145 factor D (A5D) is a cyclic lipopeptide antibiotic that shares several structural and mechanistic features with the clinically important antibiotic daptomycin, such as their requirement for calcium and phosphatidylglycerol (PG) for activity. Studies by others have suggested that daptomycin's activity is strongly inhibited by lung surfactant while A5D's activity is not. This finding has inspired efforts, albeit unsuccessful, to develop an A5D analogue that is highly active in the presence of lung surfactant and can be used for treating community acquired pneumonia (CAP). Here we demonstrate that A5D, like daptomycin, has a strong preference for the 1,2-diacyl-sn-glycero-3-phospho-1′-sn-glycerol stereoisomer (2R,2′S configuration) of PG. This PG stereoisomer was determined to be the only stereoisomer of PG in lung surfactant. Both antibiotics are completely antagonized by approximately 1−2 mol equiv of 2R,2′S-PG. Studies performed in the presence of lung surfactant revealed that the antagonism of these peptides by surfactant is mainly due to their interaction with PG and that A5D is not significantly less susceptible to inhibition by lung surfactant than daptomycin.

A Decade of Research on Daptomycin

“…By studying the interaction of daptomycin with these LUVs by using fluorescence, circular dichroism, and isothermal titration calorimetry analyses, it was deduced that both hydroxy groups influence daptomycin binding, structural transitions, and oligomerization, and that the binding pocket envelopes both hydroxy groups. 36…”

“…Studies with PG having an eight-carbon tail ( 41 ) at concentrations below the critical micelle concentration of this lipid revealed that daptomycin interacts with 41 in essentially the same manner as when the PG is incorporated into a liposome, and therefore preassembly of individual PG moieties is not a prerequisite for binding, structural transition, and oligomerization. 36…”