Between Dec 19, 2024 and Jan 2, 2025, datasets can be submitted to DRUM but will not be processed until after the break. Staff will not be available to answer email during this period, and will not be able to provide DOIs until after Jan 2. If you are in need of a DOI during this period, consider Dryad or OpenICPSR. Submission responses to the UDC may also be delayed during this time.

Browsing by Subject "Antibiotic"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Computational Insights into the Antimicrobial Mechanism of Action of Class II Bacteriocins.
    (2017-05) Kyriakou, Panagiota
    Antibiotic resistance is a global problem and poses an alarming threat to public health. Microorganisms resistant to all commercially available antibiotics have emerged, undermining the ability to fight infectious diseases. The antibiotic resistance crisis has been attributed to the overuse of antibiotics, as well as a lack of new drug development. Coordinated efforts are needed to overcome this challenge, including discovery of alternative drugs. Bacteriocins are bacteria-produced, antimicrobial peptides that are potentially powerful antibiotic drug candidates. Despite considerable scientific interest around bacteriocins, and despite their promise as potent, latent antibiotics, their everyday medical value has been negligible. In order to more effectively utilize the full potential of bacteriocins as a platform to develop new antibacterial agents, a detailed understanding of their mechanism of action is required. This mechanistic insight will offer ways to control and optimize their activity and selectivity against specific pathogens, greatly enhancing their potential for medical applications. The goal of this work is to elucidate the mechanism of action of class II bacteriocins by employing a variety of computational methods that are built around atomistic molecular dynamics simulations. First, we studied Plantaricin EF, a two-peptide class IIb bacteriocin. This bacteriocin was simulated in different environments including water, micelles, and lipid bilayers. The interaction between the two peptides that promotes dimerization, and the interaction between the dimer and the membrane were elucidated. Guided by experimental studies, a transmembrane model of the dimer embedded in the bilayer was additionally designed. Results obtained from a 1 μs long atomistic molecular dynamics simulation, demonstrated for the first time that a bacteriocin, with a narrow antimicrobial activity range, can by itself form a water (and potentially ion) permeable, toroidal pore in a lipid bilayer. This pore was characterized in detail. It is not unlikely that the mechanism of action of bacteriocins can involve poration of the membrane as well as receptor-mediation. Therefore, the interaction of a bacteriocin with its putative receptor was also examined. Lacking the structure of a receptor, we employed structure-prediction techniques in combination with docking calculations, and molecular dynamics simulations. For the first time a class II bacteriocin-receptor complex was built, setting the ground for investigating the role that receptors play in the bactericidal activity of these antimicrobial peptides. We believe that our findings could be of importance to the designing of new antibiotic agents, as it would guide the search for better bacteriocins toward peptides with improved activity and specificity, that form stable pores, increase water or ion permeability, and interact more efficiently with a receptor.
  • Thumbnail Image
    Item
    Efficacy of on-farm programs for the diagnosis and selective treatment of clinical and subclinical mastitis in dairy cattle.
    (2009-08) Lago Vázquez, José Alfonso
    The research reported in this dissertation includes two multi-state multi-herd clinical trials evaluating the efficacy of on-farm programs for the diagnosis and selective treatment of clinical and subclinical mastitis in dairy cattle. The use of an OFC system for the selective treatment of clinical mastitis during lactation reduced intramammary antibiotic use by half and tended to reduce withholding time by one day, without significant differences in days to clinical cure, bacteriological cure risk, new infection risk and ICR risk (where the ICR risk represented the presence of infection risk, clinical mastitis risk, or removal from herd risk) within 21 days after the clinical mastitis event. Similarly, there were no differences between both treatment programs in long-term outcomes such as recurrence of clinical mastitis in the same quarter, somatic cell count, milk production, and cow survival for the rest of the lactation after the clinical mastitis event. The treatment with intramammary Cephapirin Sodium of cows and quarters based on CMT results alone, or sequential testing using OFC to diagnose Gram-positives in CMT-positive quarters resulted in a higher bacteriological cure risk and reduced the ICR risk within 21 days after enrollment (significantly and only numerically, respectively for treatment each program). The implementation of both treatment programs required the administration of intramammary treatment and extended the time that milk is withhold from the market. Both programs resulted in a significantly lower clinical mastitis risk and lower milk SCC during lactation (significantly and only numerically, respectively for each treatment program). However, the implementation of both treatment programs did not result in higher milk production, improved reproductive performance or lower risk for removal from the herd. A secondary objective of both clinical trials was to validate the use of the Minnesota Easy Culture Bi-Plate System. This OFC system is a useful cow-side test to correctly identify bacterial growth, Gram-positive bacterial growth, or Gram-negative bacterial growth in quarter secretion samples from clinical mastitis cases and in CMT-positive quarter milk samples collected after parturition. Treatment decisions based on identification of bacterial growth, or Gram-positive bacterial growth specifically, were correct over 73% of the time.
  • Thumbnail Image
    Item
    Global biogeography and local adaptation of Streptomyces
    (2013-10) Schlatter, Daniel Cameron
    Streptomyces play crucial roles in key ecosystem processes including nutrient and plant disease suppression in natural and agricultural systems. Moreover, Streptomyces are major producers of clinically relevant antibiotic compounds. Despite the importance of Streptomyces in natural, agricultural, and clinical settings, we have a limited understanding of Streptomyces ecology and evolutionary biology in natural habitats. Here we characterize the function diversity and biogeography of Streptomyces to shed light on the roles of local adaptation and coevolution in structuring soil Streptomyces communities. Specifically, this work focuses on patterns of antibiotic inhibition, antibiotic resistance, resource use, and phylogeny among sympatric and allopatric Streptomyces communities from across the globe. This work documents the extensive functional diversity of Streptomyces antibiotic inhibitory, resistance, and resource use phenotypes and provides strong evidence that local adaptation, coevolution, and resource competition are crucial drivers of antibiotic inhibition and resistance among Streptomyces.