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LIPID-LIPID AND LIPID-DRUG INTERACTIONS IN BIOLOGICAL MEMBRANES
Title
LIPID-LIPID AND LIPID-DRUG INTERACTIONS IN BIOLOGICAL MEMBRANES
Creator
Martynowycz, Michael W.
Date
2016, 2016-07
Description
Interactions between lipids and drug molecules in biological membranes help govern proper biological function in organisms. The mechanisms...
Show moreInteractions between lipids and drug molecules in biological membranes help govern proper biological function in organisms. The mechanisms responsible for hydrophobic drug permeation remain elusive. Many small molecule drugs are hydrophobic. These drugs inhibit proteins in the cellular interior. The rise of antibiotic resistance in bacteria is thought to be caused by mutations in protein structure, changing drug kinetics to favor growth. However, small molecule drugs have been shown to have different mechanisms depending in the structure of the lipid membrane of the target cell. Biological membranes are investigated using Langmuir monolayers at the airliquid interface. These offer the highest level of control in the mimetic system and allow them to be investigated using complementary techniques. Langmuir isotherms and insertion assays are used to determine the area occupied by each lipid in the membrane and the change in area caused by the introduction of a drug molecule, respectively. Specular X-ray re ectivity is used to determine the electron density of the monolayer, and grazing incidence X-ray diffraction is used to determine the inplane order of the monolayer. These methods determine the affinity of the drug and the mechanism of action. Studies are presented on hydrophobic drugs with mammalian membrane mimics using warfarin along with modified analogues, called superwarfarins. Data shows that toxicity of these modified drugs are modulated by the membrane cholesterol content in cells; explaining several previously unexplained effects of the drugs. Membrane mimics of bacteria are investigated along with their interactions with a hydrophobic antibiotic, novobiocin. Data suggests that permeation of the drug is mediated by modifications to the membrane lipids, and completely ceases translocation under certain circumstances.
Ph.D. in Physics, July 2016
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MEMBRANE-DRUG INTERACTION MECHANISMS OF PEPTOID-BASED ANTIMICROBIAL AGENTS
Title
MEMBRANE-DRUG INTERACTION MECHANISMS OF PEPTOID-BASED ANTIMICROBIAL AGENTS
Creator
Andreev, Konstantin
Date
2017, 2017-05
Description
Nature is a major source of inspiration for drug design. Bacteria are developing resistance towards conventional antibiotics. Utilizing...
Show moreNature is a major source of inspiration for drug design. Bacteria are developing resistance towards conventional antibiotics. Utilizing antimicrobial peptides (AMPs) – an essential component of innate immune system, as therapeutic agents, may be a viable alternative. Unfortunately, there are a number of serious hurdles on the way towards clinical application of AMPs, including their low bioavailability, costly manufacturing process and toxicity against host cells. To address this issues, current research is focused on the design of synthetic compounds mimicking natural peptides, among which oligo(Nsubstituted glycines), or peptoids, have shown great promise. Antimicrobial drug efficacy is defined by how it interacts with the membrane of invading pathogen. The physicochemical characteristics of peptoid molecule play a crucial role in these interactions, yet their detailed structure-activity relationships remain obscure. Herein, we have demonstrated that conformational flexibility, cationic charge or hydrophobicity, are critical for oligomeric peptoids to permeate bacterial cell membranes. The outer surface of membrane was modeled by Langmuir monolayers of desired lipid composition and subjected to the constant-pressure insertion assays, epifluorescence microscopy (EFM), synchrotron X-ray reflectivity (XR) and grazing incident-angle X-ray diffraction (GIXD). Our results shed light on the critical details in peptoid mode of action. We believe this will aid in the rational design and of novel anti-infective drugs. Additionally, we have applied our experimental system to model the processes occurring at the air-water interface in lungs. Alveoli are coated by a complex lipidprotein mixture referred to as pulmonary surfactant. This facilitates respiration and prevents alveolar collapse. Patients with respiratory distress receive surfactant replacement therapy that often has the serious drawbacks. X-ray scattering data shows that the structural organization of adsorbed films correlates with surfactant delivery methods onto the respiratory surface. We anticipate that our findings will contribute to the development of novel clinical approaches for treating respiratory diseases.
Ph.D. in Biology, May 2017
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