Houston, TX 77005
2:00 p.m. Tuesday, May 28, 2013
On Campus | Alumni
Daptomycin is a lipopeptide antibiotic notably against multidrug-resistant, gram-positive pathogens. Evidence shows that the antibiotic acts neither on DNA nor on the proteins. It has been shown to insert and aggregate in the bacteria membrane; nevertheless, how the molecular interaction leads to cell death is unknown. In this work, the physical properties of interactions between daptomycin and model membranes are studied in order to understand the underlying mechanism of daptomycin. First, daptomycin’s binding affinity to membranes was found to be in proportional to Ca++ concentration. The effect of Ca++ cannot be replaced by other divalent ions such as Mg++. After binding, daptomycin was found to form lipid-peptide aggregations on DOPG-containing vesicles. PG is required for the formation of lipid-peptide aggregates, which eventually lead to membrane ruptures. Cadiolipin, another main component in bacterial membrane, cannot substitute PG to induce the same membrane defect, despite some aggregates are formed. In addition, with a fixed concentration of Ca++, it requires a minimum concentration of daptomycin to trigger the membrane defect process. The membrane defect results mainly from lipid-peptide aggregations rather than from pores forming in the membrane. Finally, x-ray data imply that daptomycin binds to the headgroup region of the bilayer, which causes membrane thinning. The elastic energy of membrane thinning elevates the energy level of daptomycin binding state that explains the transition to the aggregation state.