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Liposomes are self-assembled lipid vesicles made from phospholipids that are safe and suitable for drug encapsulation and localized drug delivery. Liposomal formulations are characterized by low toxicity and improved therapeutic index (by changing drug biodistribution) and liposomes encapsulating antifungal or anticancer drugs have already been approvedby regulatory agencies.One area of application for liposomes is localized antibiotic delivery. Antibiotics target bacteria, but specific types of infections(namely biofilms or intracellular infections)that required high or prolonged antibiotic administration have long been a challenge for antibiotic treatments. Liposomal delivery of antibiotics can improve their therapeutic index while minimizing their adverse effects. When it comes to methods of antibiotic encapsulation, however,most reports to date follow the methods developed for anticancer drugs for encapsulating antibiotics. This oversight causes discrepancies in the literature, mainly because of the significantly different chemical structures of antibiotics and cancer drugs. Furthermore, most antibiotics are highly sensitive to temperature fluctuations, which is concerning, given most liposomal preparation methods involve extreme temperature fluctuations. The aim of my thesis was to explore these missing links in the literature by answering these questions: (1) will liposome preparation method affect encapsulation efficiency of antibiotics?And (2) does liposomal preparation method adversely affect the efficacy of antibiotics?Investigating these questions led to further insight into the optimal process for achieving high encapsulation efficiencies for different antibiotics and for further avoiding damage due to harsh processing conditions. We found that different preparation methods are better for different types of antibiotics, being the one that promotes a large aqueous space better for hydrophilic drugs and the one that creates oligolamellar and large unilamellar vesicles better for more hydrophobic drugs. The steps in liposome preparation methods such as heating and sonication can affect the stability of the antibiotics. / Thesis / Master of Applied Science (MASc) / When antibiotics are administered, orally or intravenously, they should pass through different tissues to arrive to the site of infection; this can cause dilution and/or intoxication. To overcome these problems, drug delivery vehicles have been used to encapsulate and deliver antibiotics, improving their therapeutic index while minimizing their adverse effects. Liposomes are vesicles composed of at least one lipid bilayer, with an inner aqueous compartment. Liposomes are an attractive vehicle to deliver antibiotics because they can encapsulate both hydrophobic and hydrophilic antibiotics, they have low toxicity, and they can change the bio-distribution of the drug. In mythesis, I addressedtwo main questions regarding liposomal antibiotic encapsulation:(1) will liposome preparation method affect encapsulation efficiency of antibiotics, and(2) does liposome preparation method adversely affect the efficacy of antibiotics. While investigating these questions,I also identified certain outstanding biases in the liposomal characterization methods.

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Sec translocon is the major machinery for protein translocation in E.coli including SecYEG, SecA and other Sec proteins. It is generally assumed that during translocation process, SecYEG serves as a protein-conducting channel and transports the protein across membranes by using SecA ATPase as driving force. However, previous work suggested that protein translocation can occur without SecYEG. In order to understand the role of SecA in this SecYEG-independent process, we use voltage clamp recording as a tool to study the ionic activity of SecA-dependent protein-conducting channel. In a major deviation from the conventional view, we found that SecA alone is sufficient to promote the channel activity with liposomes made of E.coli phospholipids in both whole cell recording in the oocytes and in the single channel recording with patch clamp. The activity is strictly dependent on the presence of functional SecA, including those from different species of bacteria. However, this SecA-alone dependent channel activity is less efficient compared to the membranes containing SecYEG. Furthermore, the channel activity loses the signal peptide specificity. Addition of purified SecYEG restores the signal peptide specificity as well as the efficiency. This channel activity is more sensitive to SecA-specific inhibitors compared with membranes containing wild-type SecYEG but is less sensitive to membranes containing suppressor proteins. This is the first time it has been shown that SecA binds to lipid low-affinity site and functions as a protein-conducting channel. To further characterize the structural roles of SecA as the core of the channel, we use several SecA variants to reconstitute with liposomes to determine the domains involved in forming functional channels. Using deletion truncated domains of 901 residues SecA and liposomes in the oocytes recordings, we identify two critical SecA domains for the formation of pore channel activity: with phospholipids alone, and for interacting with SecYEG to gain higher activity. These data provide fundamental understanding for the SecA-dependent protein –conducting channels. Our findings also suggest the possible evolution process on the protein translocation pathways from prokaryotes through eukaryotes.

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Akademisk avhandling--analytical and marine chemistry--Göteborg university, 2003. / Bibliogr. p. 74-82.

Thesis (Ph. D.)--University of Wisconsin--Madison, 2003. / Includes bibliographical references (p. 103-116). Also available on the Internet.