Genetic Determinants Involved in Acquisition of Iron in the Opportunistic Pathogen Mycobacterium abscessus

Author

Manal F. Farhat, The Graduate Center, City University of New YorkFollow

Date of Degree

2-2023

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Luis E.N. Quadri

Committee Members

Theodore Muth

Juergen Polle

Peter Lipke

Venkatesan Jayaprakash

Subject Categories

Bacterial Infections and Mycoses | Bacteriology | Biology | Diseases | Microbiology | Molecular Biology | Molecular Genetics | Pathogenic Microbiology

Keywords

mycobacteria, Mycobacterium abscessus, Mycobacterium tuberculosis, iron, ESX-3, siderophores

Abstract

The opportunistic pathogen Mycobacterium abscessus subsp. abscessus (Mab) has become an emerging public health threat due to the increasing number of Mab-associated chronic pulmonary disease cases. Infection cure rates are only 50% due to the complex resistance of Mab to most antimicrobial drugs and chemotherapy.

Deeper knowledge of Mab biology is needed to illuminate potential candidates for development of improved therapeutics against Mab infections. The ESX-3 type VII protein secretion system of Mab plays an important role in host inflammatory and pathological responses during infection.

In this study, we demonstrate a functional link between the ESX-3 secretion system and an iron uptake system based on an unusual mycobactin-type siderophore (designated MBT Ab), and exploit this link to implement a large genetic screen for transposon mutants with an impaired ESX-3. Most mutants we identified carry insertions in genes encoding predicted ESX-3 secretion machinery components or potential ESX-3 substrates.

The mutant isolates overproduce MBT Ab, a trait consistent with an iron uptake defect. To determine whether MAB_2247c gene expression, a putative homolog of Mycobacterium tuberculosis mbtA gene located in the mbt gene cluster, is related to the synthesis of MBT Ab under iron deprivation conditions, we created a targeted Mab mbtA deletion mutant. The collection of novel mutants generated in this study will facilitate future research to better understand the role of the ESX-3 secretion system and its interplay with the siderophore system.

Recommended Citation

Farhat, Manal F., "Genetic Determinants Involved in Acquisition of Iron in the Opportunistic Pathogen Mycobacterium abscessus" (2023). CUNY Academic Works.
https://academicworks.cuny.edu/gc_etds/5139