Abstract
Since mass production of antimicrobial agents was established 70 years ago these
miracle-drugs have been integral tools in modern medicine, saving an uncountable number of lives. However, bacteria are now consistently and with alarming rates developing resistance towards common antibiotics. Very few new drugs have been marketed over the last decades, making it impossible to keep pace with the disturbing levels of multi-drug resistant bacteria. Research in the area of novel drugs, which are less prone to induce resistance, and in-depth knowledge on their uptake mechanisms is thus of paramount importance in the fight against the horrifying thought of an approaching post-antibiotic era.
The work presented in this thesis sheds light on the interaction mechanism of
novel dendritic molecules synthesized from antimicrobial peptides. These types
of molecules interact non-specifically with lipid membranes or highly conserved
motifs, effectively making resistance due to mutations less likely to develop and
spread. For this we studied the conditions to form supported lipid bilayers with
basic systems and further established a protocol for producing biomimetic bacterial model membranes via the vesicle fusion method, which presents improved means for studying drug-membrane interactions in the future.
The interaction mechanism of a family of dendrimers was examined and in particular one dendrimer (BALY) was extensively studied by the combined use of quartz crystal microbalance, atomic force microscopy and neutron reection. The application of several complementary surface-sensitive techniques allowed for systematically addressing the interface-related processes and gain insights into different aspects of the interaction. BALY was found to interact via a
uidity-dependent mechanism. It inserted into the outer leaet of gel phase membranes and caused the formation of thinned domains. In uid membranes it integrated into the upper membrane leaet and caused a change of lipid packing and the formation of spherical aggregates that solubilized the membrane over time. Phase separation of the membrane into uid and gel domains or forcing a gel phase membrane pre-equilibrated with dendrimers to undergo a phase transition, enhanced the interaction and led to membrane thinning and dendrimer translocation. These latter models could to a higher degree resemble the heterogenous lateral nanoscale structure of native cell membranes.
miracle-drugs have been integral tools in modern medicine, saving an uncountable number of lives. However, bacteria are now consistently and with alarming rates developing resistance towards common antibiotics. Very few new drugs have been marketed over the last decades, making it impossible to keep pace with the disturbing levels of multi-drug resistant bacteria. Research in the area of novel drugs, which are less prone to induce resistance, and in-depth knowledge on their uptake mechanisms is thus of paramount importance in the fight against the horrifying thought of an approaching post-antibiotic era.
The work presented in this thesis sheds light on the interaction mechanism of
novel dendritic molecules synthesized from antimicrobial peptides. These types
of molecules interact non-specifically with lipid membranes or highly conserved
motifs, effectively making resistance due to mutations less likely to develop and
spread. For this we studied the conditions to form supported lipid bilayers with
basic systems and further established a protocol for producing biomimetic bacterial model membranes via the vesicle fusion method, which presents improved means for studying drug-membrane interactions in the future.
The interaction mechanism of a family of dendrimers was examined and in particular one dendrimer (BALY) was extensively studied by the combined use of quartz crystal microbalance, atomic force microscopy and neutron reection. The application of several complementary surface-sensitive techniques allowed for systematically addressing the interface-related processes and gain insights into different aspects of the interaction. BALY was found to interact via a
uidity-dependent mechanism. It inserted into the outer leaet of gel phase membranes and caused the formation of thinned domains. In uid membranes it integrated into the upper membrane leaet and caused a change of lipid packing and the formation of spherical aggregates that solubilized the membrane over time. Phase separation of the membrane into uid and gel domains or forcing a gel phase membrane pre-equilibrated with dendrimers to undergo a phase transition, enhanced the interaction and led to membrane thinning and dendrimer translocation. These latter models could to a higher degree resemble the heterogenous lateral nanoscale structure of native cell membranes.
| Original language | English |
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| Publisher | Department of Chemistry, Faculty of Science, University of Copenhagen |
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| Publication status | Published - 2014 |