How daptomycin kills multi-drug resistant bacteria
Mode-of-action: several daptomycin molecules (top; blue) push themselves in between the membrane lipids (grey and/or red) using their tails. While doing this, they attract fluid membrane lipids (red), consequently releasing an important enzyme (green)
The antibiotic daptomycin is often the last-resort treatment of multidrug-resistant bacteria. Up to now, it has been unclear how the drug works. A new study conducted with the DZIF now sheds light on this. According to the study, daptomycin inhibits the pathogen’s cell membrane synthesis through a previously unknown mechanism.
Daptomycin is a so-called last resort or emergency antibiotic: it is often considered the last choice of treatment for multidrug-resistant bacteria such as the MRSA pathogens. Meanwhile, the substance has been approved in Germany for over ten years. Up to now, there have been different hypotheses on its mode of action. “This is very unusual,” emphasizes Prof Tanja Schneider from the Institute of Pharmaceutical Microbiology at the University of Bonn and the DZIF: “We have predominantly been in the dark about daptomycin’s mode of action even after decades of intensive research, in contrast to all other approved antibiotics where the mechanisms of action are known.”
The scientist now shed a little light on this with their study, according to which daptomycin inhibits the dangerous pathogen’s cell membrane synthesis with a tricky mechanism. Besides the Universities of Bonn and Amsterdam, the Ruhr University Bochum, Newcastle University and the German Center for Infection Research (DZIF) were involved.
Daptomycin interferes with the membrane
Daptomycin thoroughly interferes with the structure of the cell membrane. The antibiotic looks similar to a tadpole with a big head and a short tail. From outside, this tail dips into the bacterial membrane. The head needs space and pushes the lipids aside a little. “This evidently only occurs at specific membrane locations where there is sufficient fluidity,” explains Schneider.
Under certain conditions, daptomycin molecules have the tendency to cluster. These aggregates require particularly fluid areas of the membrane. For this purpose, similar to a magnet, they attract further mobile lipids, seriously disrupting the membrane structure. Proteins that are usually attached to the inside of the lipid membrane can detach and lose their function. “This includes enzymes that catalyse bacterial cell membrane synthesis,” explain Schneider’s colleagues Dr Anna Müller and Dr Fabian Grein. “Without this protective envelope, these pathogens die.”
Understanding an antibiotic’s precise mechanism of action is extremely important. “This, for example, helps us better decide with which other antibiotics the substance could be sensibly combined, or estimate the risk of developing resistance,” emphasizes Tanja Schneider.
