서브메뉴
검색
Harnessing Microbial Warfare to Identify Products Lethal to Pathogenic Free-Living Amoebae by Pseudomonas aeruginosa
Harnessing Microbial Warfare to Identify Products Lethal to Pathogenic Free-Living Amoebae by Pseudomonas aeruginosa
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211151026
- ISBN
- 9798383482759
- DDC
- 576
- 서명/저자
- Harnessing Microbial Warfare to Identify Products Lethal to Pathogenic Free-Living Amoebae by Pseudomonas aeruginosa
- 발행사항
- [Sl] : Yale University, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 175 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-01, Section: B.
- 주기사항
- Advisor: Kazmierczak, Barbara I.
- 학위논문주기
- Thesis (Ph.D.)--Yale University, 2024.
- 초록/해제
- 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.
- 일반주제명
- Microbiology
- 일반주제명
- Chemistry
- 키워드
- Acanthamoeba
- 키워드
- Natural products
- 키워드
- Pseudomonas
- 키워드
- Small molecules
- 기타저자
- Yale University Microbiology in MD/PhD Program
- 기본자료저록
- Dissertations Abstracts International. 86-01B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
008250123s2024 us c eng d■001000017160478
■00520250211151026
■006m o d
■007cr#unu||||||||
■020 ▼a9798383482759
■035 ▼a(MiAaPQ)AAI30996931
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a576
■1001 ▼aFlynn, Carrie Anne.
■24510▼aHarnessing Microbial Warfare to Identify Products Lethal to Pathogenic Free-Living Amoebae by Pseudomonas aeruginosa
■260 ▼a[Sl]▼bYale University▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a175 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-01, Section: B.
■500 ▼aAdvisor: Kazmierczak, Barbara I.
■5021 ▼aThesis (Ph.D.)--Yale University, 2024.
■520 ▼aAcanthamoeba 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.
■590 ▼aSchool code: 0265.
■650 4▼aMicrobiology
■650 4▼aChemistry
■653 ▼aAcanthamoeba
■653 ▼aFree-living amoeba
■653 ▼aMicrobial interactions
■653 ▼aNatural products
■653 ▼aPseudomonas
■653 ▼aSmall molecules
■690 ▼a0410
■690 ▼a0485
■71020▼aYale University▼bMicrobiology in MD/PhD Program.
■7730 ▼tDissertations Abstracts International▼g86-01B.
■790 ▼a0265
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17160478▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
