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Characterization of the Effect of Extracellular Purines on c-di-GMP Signaling and Substrate Identification of Nucleobase Transporters in Pseudomonas aeruginosa
Characterization of the Effect of Extracellular Purines on c-di-GMP Signaling and Substrate Identification of Nucleobase Transporters in Pseudomonas aeruginosa
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211152138
- ISBN
- 9798384018131
- DDC
- 576
- 저자명
- Kennelly, Corey.
- 서명/저자
- Characterization of the Effect of Extracellular Purines on c-di-GMP Signaling and Substrate Identification of Nucleobase Transporters in Pseudomonas aeruginosa
- 발행사항
- [Sl] : Northwestern University, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 201 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-02, Section: B.
- 주기사항
- Advisor: Prindle, Arthur.
- 학위논문주기
- Thesis (Ph.D.)--Northwestern University, 2024.
- 초록/해제
- 요약Pseudomonas aeruginosa is a frequently multidrug-resistant opportunistic pathogen, a common cause of healthcare-acquired infections, and a premier model organism used for the study of biofilms. This dissertation is composed of two distinct yet complementary projects which have improved our understanding of nucleotide metabolism in this clinically relevant organism.In the first project, the relationship between environmental purines, c-di-GMP signaling, and biofilm formation was investigated. I found that environmental purines reduced c-di-GMP and biofilm formation in a salvage-dependent manner. Based on further investigation, this is likely caused by upstream metabolic control of c-di-GMP precursors. This mechanism is unique because previously identified cues alter c-di-GMP levels by modulating activity of enzymes directly involved in c-di-GMP synthesis or degradation. I also demonstrated that (p)ppGpp likely allows P. aeruginosa to maintain stable levels of GTP and c-di-GMP, particularly in the presence of extracellular guanylate compounds. These findings may have broad significance because these responses may also occur in other organisms. Overall, this first project reveals that purines can act as a cue for bacteria to shift their lifestyle away from the recalcitrant biofilm state by upstream metabolic control of c-di-GMP signaling.In the second project, the method by which environmental purines and pyrimidines are transported was investigated. Little was previously known about the substrate specificity of the 13 putative nucleobase transporters in P. aeruginosa. Using a combination of genetic and chemical approaches, I identified substrates for 10 putative nucleobase transporters in P. aeruginosa. Specifically, the sole allantoin transporter as well as transporters for adenine, guanine, xanthine, uric acid, cytosine, thymine, uracil, and dihydrouracil were identified. Furthermore, at least 5 of the 13 transporters transport hypoxanthine, a molecule which was found to affect biofilm formation in the first project. The redundancy in transport of this molecule highlights its apparent importance. Transporters important for uptake of the potential antimicrobial therapeutics 8-azaguanine, 6-thioguanine, 5-fluorocytosine, and 5-fluorouracil were also identified. The strains generated for this project can act as new tools to address previously difficult-to-test hypotheses relating to nucleobase transport. Overall, this second project provides an initial characterization of the putative nucleobase transporters in P. aeruginosa, significantly advancing our understanding of nucleobase transport in this clinically relevant organism.
- 일반주제명
- Microbiology
- 일반주제명
- Biochemistry
- 일반주제명
- Biology
- 일반주제명
- Molecular biology
- 키워드
- Biofilms
- 키워드
- Purines
- 키워드
- Pyrimidines
- 기타저자
- Northwestern University Driskill Graduate Training Program in Life Sciences
- 기본자료저록
- Dissertations Abstracts International. 86-02B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211152138
■006m o d
■007cr#unu||||||||
■020 ▼a9798384018131
■035 ▼a(MiAaPQ)AAI31484473
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a576
■1001 ▼aKennelly, Corey.▼0(orcid)0009-0008-9308-5387
■24510▼aCharacterization of the Effect of Extracellular Purines on c-di-GMP Signaling and Substrate Identification of Nucleobase Transporters in Pseudomonas aeruginosa
■260 ▼a[Sl]▼bNorthwestern University▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a201 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-02, Section: B.
■500 ▼aAdvisor: Prindle, Arthur.
■5021 ▼aThesis (Ph.D.)--Northwestern University, 2024.
■520 ▼aPseudomonas aeruginosa is a frequently multidrug-resistant opportunistic pathogen, a common cause of healthcare-acquired infections, and a premier model organism used for the study of biofilms. This dissertation is composed of two distinct yet complementary projects which have improved our understanding of nucleotide metabolism in this clinically relevant organism.In the first project, the relationship between environmental purines, c-di-GMP signaling, and biofilm formation was investigated. I found that environmental purines reduced c-di-GMP and biofilm formation in a salvage-dependent manner. Based on further investigation, this is likely caused by upstream metabolic control of c-di-GMP precursors. This mechanism is unique because previously identified cues alter c-di-GMP levels by modulating activity of enzymes directly involved in c-di-GMP synthesis or degradation. I also demonstrated that (p)ppGpp likely allows P. aeruginosa to maintain stable levels of GTP and c-di-GMP, particularly in the presence of extracellular guanylate compounds. These findings may have broad significance because these responses may also occur in other organisms. Overall, this first project reveals that purines can act as a cue for bacteria to shift their lifestyle away from the recalcitrant biofilm state by upstream metabolic control of c-di-GMP signaling.In the second project, the method by which environmental purines and pyrimidines are transported was investigated. Little was previously known about the substrate specificity of the 13 putative nucleobase transporters in P. aeruginosa. Using a combination of genetic and chemical approaches, I identified substrates for 10 putative nucleobase transporters in P. aeruginosa. Specifically, the sole allantoin transporter as well as transporters for adenine, guanine, xanthine, uric acid, cytosine, thymine, uracil, and dihydrouracil were identified. Furthermore, at least 5 of the 13 transporters transport hypoxanthine, a molecule which was found to affect biofilm formation in the first project. The redundancy in transport of this molecule highlights its apparent importance. Transporters important for uptake of the potential antimicrobial therapeutics 8-azaguanine, 6-thioguanine, 5-fluorocytosine, and 5-fluorouracil were also identified. The strains generated for this project can act as new tools to address previously difficult-to-test hypotheses relating to nucleobase transport. Overall, this second project provides an initial characterization of the putative nucleobase transporters in P. aeruginosa, significantly advancing our understanding of nucleobase transport in this clinically relevant organism.
■590 ▼aSchool code: 0163.
■650 4▼aMicrobiology
■650 4▼aBiochemistry
■650 4▼aBiology
■650 4▼aMolecular biology
■653 ▼aBiofilms
■653 ▼aNucleotide signaling
■653 ▼aPseudomonas aeruginosa
■653 ▼aPurines
■653 ▼aPyrimidines
■690 ▼a0410
■690 ▼a0487
■690 ▼a0306
■690 ▼a0307
■71020▼aNorthwestern University▼bDriskill Graduate Training Program in Life Sciences.
■7730 ▼tDissertations Abstracts International▼g86-02B.
■790 ▼a0163
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17163128▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
