Browsing by Author "Kim, Haeun (Sara)"

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    Screening and Characterization of Antimicrobial Compounds and Material against Vibrio cholerae
    (2023-10-12) Kim, Haeun (Sara); MacDonald, Justin A.; Dong, Tao G.; DeVinney, Rebekah; Schriemer, David
    Antibiotic resistance (ABR) is a multisectoral global threat. With an increasing number of critical pathogens acquiring resistance against multiple classes of antibiotics, we face the terror of the post-antibiotic era. Vibrio cholerae, the cholera-causing pathogen, is no exception to the menace of multi-drug resistance. Strains from worldwide outbreaks have shown resistance to all antibiotics used to treat cholera, including ciprofloxacin. With cholera being prevalent in developing countries and regions affected by natural and anthropogenic disasters, an increase in fatalities is a rising concern in these areas with the number of effective antibiotics rapidly decreasing. This thesis explores the alternative approaches to treating cholera and controlling the spread of ABR pathogens in the environment. First, a library of 400 chemical compounds with antimicrobial activities, the Pathogen Box, is screened for compounds that exhibit killing or inhibiting activities against V. cholerae. Two compounds, MMV687807 and MMV675968, demonstrated bactericidal and bacteriostatic activity against the pathogen with high efficacy, respectively. RNA-seq analyses of V. cholerae treated with each compound revealed that their impact on multiple cellular functions, including carbon metabolism and iron homeostasis. Whole genome sequencing of spontaneous resistance mutants uncovered that activation of an efflux system via mutation to their regulator confers resistance to MMV687807. MMV675968 was identified to function similar to trimethoprim, targeting the dihydrofolate reductase of V. cholerae. This compound has the potential to be developed as a trimethoprim replacement with a minimum inhibitory concentration lower by 14-fold. Next, the antibacterial property of a newly synthesized cellulose aerogel cross-linked with different concentrations of silver/lignin nanoparticles (lignin only, 1Ag/L, 2Ag/L, and 3Ag/L) was studied in collaboration with Xiao He. Each aerogel was incubated with Gram-positive or Gram-negative pathogens, and surviving colonies were counted. Increase in killing efficiency was observed with increasing concentration of Ag/L nanoparticles. The cellulose aerogel with 3 Ag/L exhibited exceptional killing across all tested species: E. coli: > 99.99%, P. aeruginosa: > 99.9%, V. cholera: > 99.99%, S. aureus: > 99.99%, B. subtilis: > 97.4%. Through screening small molecules and exploring synthetic material cross-linked with nanoparticles, this thesis demonstrates the significance of developing new tools to inhibit bacterial pathogens and fight the spread of ABR.