자료유형  

 학위논문

Control Number  

0017161755

International Standard Book Number  

9798382785004

Dewey Decimal Classification Number  

576

Main Entry-Personal Name  

McGowen, Kerry Alexandra.

Publication, Distribution, etc. (Imprint  

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

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

189 p.

General Note  

Source: Dissertations Abstracts International, Volume: 85-12, Section: B.

General Note  

Advisor: Rubin, Eric J.

Dissertation Note  

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

Summary, Etc.  

요약The Mycobacterium genus contains several pathogenic species that cause significant human morbidity and mortality. This includes Mycobacterium tuberculosis (Mtb), the causative pathogen of one of the deadliest infectious diseases in the world, tuberculosis (TB), as well as several nontuberculous mycobacteria (NTM) species, such as Mycobacterium abscessus, that can cause opportunistic lung infections. Pathogenic mycobacteria generally exhibit high levels of antibiotic resistance to multiple classes of antibiotics. However, the current understanding of the genetic determinants of antibiotic resistance in mycobacteria remains poor, and this is further complicated by an incomplete understanding of the mechanisms of action for many antibiotics that are currently used to treat mycobacterial infections. This dissertation aims to identify and characterize the molecular determinants of antibiotic susceptibility in mycobacteria. Overall, we seek to better understand the mechanisms of resistance and drug action of two important anti-mycobacterial antibiotics, linezolid and pretomanid. In Chapter 1, we discuss our current understanding and outstanding questions regarding intrinsic and acquired antibiotic resistance in mycobacteria. We examine approaches to discover novel genetic determinants, and we discuss how elucidating the mechanisms of action can also help uncover potentiation strategies. In Chapter 2, we perform a genetic screen to uncover the genetic determinants of intrinsic linezolid resistance in M. abscessus. We discover multiple transmembrane proteins that likely play a role in maintaining cell wall integrity, which prevents permeability to linezolid. Furthermore, we also find a novel M. abscessus-specific efflux pump, MAB_2303, that has a direct role linezolid efflux. Together these findings suggest that targeting these transmembrane proteins or MAB_2303 could be promising avenues for potentiating linezolid activity in M. abscessus. In Chapter 3, we characterize an ABC-F family protein, MAB_2736c, in M. abscessus that confers resistance to linezolid, chloramphenicol, and macrolides. We find that MAB_2736c likely confers resistance through a ribosomal protection mechanism that disrupts linezolid's ability to interact with the ribosome. Our results highlight that ARE-ABC-F proteins are important determinants of intrinsic resistance in mycobacteria. In Chapter 4, we perform a genetic screen in mice to determine differentially required Mtb genes for survival upon pretomanid treatment. We find that the nucleotide excision repair (NER) pathway is essential for Mtb survival upon pretomanid only in physiologically relevant conditions that mimic the infection environment. Additionally, we discover that in these conditions pretomanid causes an increased mutational burden that is heightened in NER pathway mutants. Together, this reveals that DNA damage is a novel in vivo mechanism of action for pretomanid. Lastly, in Chapter 5, we close with a summary of the implications of this body of work, discuss future directions, and define ways in which our findings can be used to develop new strategies to better mycobacterial therapeutics. Ultimately, this work enriches our understanding of the molecular determinants of antibiotic susceptibility in mycobacteria, which is critical for developing alternative therapeutic strategies to combat mycobacterial infections.

Subject Added Entry-Topical Term  

Microbiology.

Subject Added Entry-Topical Term  

Genetics.

Subject Added Entry-Topical Term  

Pathology.

Subject Added Entry-Topical Term  

Immunology.

Index Term-Uncontrolled  

Antibiotic resistance

Index Term-Uncontrolled  

Antibiotic susceptibility

Index Term-Uncontrolled  

Mycobacteria

Index Term-Uncontrolled  

Genetic determinants

Index Term-Uncontrolled  

Nucleotide excision repair

Added Entry-Corporate Name  

Harvard University Biological Sciences in Public Health

Host Item Entry  

Dissertations Abstracts International. 85-12B.

Electronic Location and Access  

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Control Number  

joongbu:654778