자료유형  

 학위논문

Control Number  

0017160478

International Standard Book Number  

9798383482759

Dewey Decimal Classification Number  

576

Main Entry-Personal Name  

Flynn, Carrie Anne.

Publication, Distribution, etc. (Imprint  

[S.l.] : Yale University., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

175 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-01, Section: B.

General Note  

Advisor: Kazmierczak, Barbara I.

Dissertation Note  

Thesis (Ph.D.)--Yale University, 2024.

Summary, Etc.  

요약Acanthamoeba castellanii is a free-living amoeba (FLA) that causes untreatable, fatal infections of the central nervous system. FLA are ubiquitous in the environment, where they graze upon bacteria such as Pseudomonas aeruginosa. We interrogated P. aeruginosa-under evolutionary pressure to defend against amoebal grazing-as a producer of amoebicidal compounds that could serve as leads for new and urgently needed drugs to treat amoeba infections in humans.To accomplish this, we developed novel methods to quantify killing of A. castellanii trophozoites, pseudocysts, and cysts. Together, these high throughput, reproducible, and extensively validated assays provide a robust platform to measure viability of all Acanthamoeba life forms, the first in the field for pseudocysts and cysts. Using these assays, we tested the amoebicidal activity of all clinically relevant drug classes on both trophozoites and cysts.We additionally utilized these methods to demonstrate that P. aeruginosa, through complementary secreted molecules, uses a one-two punch to kill both the trophozoite and cyst forms of A. castellanii. We identified bacterial genes essential for killing by screening an arrayed P. aeruginosa transposon insertion mutant library for amoebicidal activity and surprisingly discovered that a shared pathway-fatty acid synthesis initiation-contributes to killing both trophozoites and cysts. Using an innovative biochemical pipeline, we discovered 22 candidate amoebicidal molecules. The structure of these compounds led to the identification of two clinically used drugs-an antibiotic and an antiemetic-that are lethal to A. castellanii in vitro.These studies provide essential tools to study FLA and advance our understanding of the chemical weapons P. aeruginosa uses to combat A. castellanii predation in the environment. These P. aeruginosa natural products have already led to the identification of two new, clinically available drugs with amoebicidal activity and are additional leads for novel therapeutic agents to treat devastating human infections by FLA.

Subject Added Entry-Topical Term  

Microbiology.

Subject Added Entry-Topical Term  

Chemistry.

Index Term-Uncontrolled  

Acanthamoeba

Index Term-Uncontrolled  

Free-living amoeba

Index Term-Uncontrolled  

Microbial interactions

Index Term-Uncontrolled  

Natural products

Index Term-Uncontrolled  

Pseudomonas

Index Term-Uncontrolled  

Small molecules

Added Entry-Corporate Name  

Yale University Microbiology in MD/PhD Program

Host Item Entry  

Dissertations Abstracts International. 86-01B.

Electronic Location and Access  

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Control Number  

joongbu:657055