A. James Clark School of Engineering

Permanent URI for this communityhttp://hdl.handle.net/1903/1654

The collections in this community comprise faculty research works, as well as graduate theses and dissertations.

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    Elimination of Bloodstream Infections Associated with Candida albicans Biofilm in Intravascular Catheters
    (MDPI, 2015-06-29) Akbari, Freshta; Kjellerup, Birthe Veno
    Intravascular catheters are among the most commonly inserted medical devices and they are known to cause a large number of catheter related bloodstream infections (BSIs). Biofilms are associated with many chronic infections due to the aggregation of microorganisms. One of these organisms is the fungus Candida albicans. It has shown to be one of the leading causes of catheter-related BSIs. The presence of biofilm on intravascular catheters provide increased tolerance against antimicrobial treatments, thus alternative treatment strategies are sought. Traditionally, many strategies, such as application of combined antimicrobials, addition of antifungals, and removal of catheters, have been practiced, but they were not successful in eradicating BSIs. Since these fungal infections can result in significant morbidity, mortality, and increased healthcare cost, other promising preventive strategies, including antimicrobial lock therapy, chelating agents, alcohol, and biofilm disruptors, have been applied. In this review, current success and failure of these new approaches, and a comparison with the previous strategies are discussed in order to understand which preventative treatment is the most effective in controlling the catheter-related BSIs.
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    PROTEIN AND PEPTIDE ENGINEERING FOR IMPROVING THERAPIES FOR APPLICATIONS IN HUMAN HEALTH
    (2018) Moghaddam-Taaheri, Parisa; Karlsson, Amy J; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    The work in this dissertation focuses on protein and peptides engineering for improving therapies for applications in human health. First, we describe a directed evolution approach to engineer antibody fragments to bind to intracellular targets. An antibody fragment library was displayed using the twin arginine translocation inner-membrane display pathway, in order to allow only antibodies that are well-folded in the reducing cytoplasmic environment to be screened for binding. Displayed libraries were screened for binding to the apoptosis inhibitor survivin, and scFv cytoplasmic solubility and specificity was characterized. Though the antibodies isolated through this method displayed strong intracellular folding and high binding to survivin, they exhibited non-specific binding as well. We improved the screening approach by using whole-plasmid PCR to recover sequences of isolated antibodies. Additional improvements to the screening process to increase stringency will allow better isolation of antibodies with high affinity and specificity for their target. In a rational design approach, we designed an antimicrobial peptide-based approach for the treatment of candidiasis. Candida albicans is a commensal organism that resides asymptomatically in the body. This opportunistic pathogen can overgrow and cause potentially fatal bloodstream infections. C. albicans biofilms that colonize implanted devices exhibit increased resistance to antimicrobial treatments and current antifungal treatments contribute to the rise of resistant strains of C. albicans or may cause toxicity. Thus, there is a clinical need for new or improved antifungal therapeutics to treat C. albicans infections. Histatin-5 (Hst-5) is an antimicrobial peptide secreted by the salivary glands that exhibits antifungal activity against C. albicans. Hst-5 can, however, be degraded by secreted aspartic proteases (Saps) produced by C. albicans cells, reducing its antifungal activity. Amino acid substitutions made to Hst-5 reduced the likelihood of proteolytic degradation to better maintain antifungal activity. Of these modifications, the K11R-K17R and E16R peptides showed enhanced antifungal activity in preventing C. albicans biofilm formation and eradicating preformed biofilms as compared to parent Hst-5. The improvements to methods and experimental findings in this research contribute to the improvement of therapies to treat human disease.
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    Inhibitors of Autoinducer-2 Quorum Sensing and Their Effect on Bacterial Biofilm Formation
    (2007-07-31) Lennen, Rebecca Melissa; Bentley, William E; Chemical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Bacteria utilize small signaling molecules, or autoinducers, to regulate their gene expression in tandem by a process termed quorum sensing. The gene encoding the synthase for autoinducer-2 (AI-2), luxS, is conserved in dozens of diverse bacteria. Behaviors controlled by AI-2 include virulence, motility, toxin production, and biofilm formation. The development of therapies that interfere with AI-2 quorum sensing are attractive for targeting biofilms, which exhibit inherent resistance to most antibiotics and biocidal agents. In this study, in vitro synthesized AI-2, LuxS inhibitors, and (5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone were screened for their effect on biofilm formation in Escherichia coli, Bacillus cereus, and Listeria innocua. The LuxS inhibitors were found to have no influence on biofilm formation in any of the screened species, but reduced exponential phase AI-2 production in Listeria innocua. The brominated furanone significantly inhibited growth in B. cereus and L. innocua, and under certain conditions preferentially inhibited biofilm formation independently from growth.