Year of Award

2018

Document Type

Thesis

Degree Type

Master of Science (MS)

Degree Name

Cellular, Molecular and Microbial Biology

Department or School/College

Microbiology

Committee Chair

Dr. Nigel Priestley

Committee Co-chair

Dr. Michael Minnick

Commitee Members

Dr. Stephen Lodmell

Keywords

S. aureus, antibiotic, photoaffinity labeling, bioinformatics, synthesis

Publisher

University of Montana

Subject Categories

Bioinformatics | Microbiology | Organic Chemistry

Abstract

Staphylococcus aureus is a Gram-positive bacterial pathogen responsible for nosocomial and community-acquired infections that can quickly acquire antibiotic resistance. We have identified a novel triazole antimicrobial 31G12 based on the natural product core of nonactin isolated from the fermentation of Streptomyces griseus, that is active against many Gram-positive bacteria as well as antibiotic resistant methicillin-resistant S. aureus and vancomycin-resistant Enterococcus. The synthesis and characterization indicate that 31G12 exists as a mixture of two rotamers at room temperature and displays bacteriostatic activity against S. aureus with moderate mammalian cell toxicity. We have currently identified potential protein targets of 31G12 in S. aureus via an interdisciplinary approach to the target elucidation. First, a chemical proteomic strategy using photoaffinity labeling revealed a potential target protein at approximately 110 kDa when visualized via western blot and in-gel scans. Second, whole-genome sequencing and a bioinformatics approach revealed two potential proteins, thioredoxin-fold protein and L11 methyltransferase to be good candidates based on dose-response curves. Although the mode of action has not been established, this work provides a rational framework to expand the efficacy of this novel class of antimicrobials through structure-based drug design to improve potency against Gram-positive bacteria and reduce mammalian cell toxicity.

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© Copyright 2018 Larissa A. Walker