Author

Farah Shamma

Graduation Semester and Year

2021

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Quantitative Biology

Department

Biology

First Advisor

Cheney Cara Boutte

Abstract

Mycobacterium tuberculosis (Mtb) is the causative agent of the deadly infection Tuberculosis (TB). The current standard antibiotic regimen for TB treatment combines fours drugs to be taken for at least six months. Mtb shows intrinsic phenotypic tolerance to antibiotics contributing to the long treatment regimen. In addition, Mtb cells can achieve a non-replicating state exhibiting antibiotic tolerance, reduced metabolism and altered cell wall staining. The changes in the cell wall and reduced permeability to antibiotics in stressed cells suggest that the regulation of the cell wall is a major contributor to antibiotic tolerance. The mycobacterial cell wall consists of covalently cross-linked peptidoglycan, arabinogalactan and mycolic acid layers. While this complex architecture is well studied, not much is known about how cell wall is regulated in stress. Mycobacteria use reversible Serine/Threonine phosphorylation as an important mechanism to regulate their cell wall. In contrast to the eleven Serine/Threonine protein kinases (STPKs), which regulate a number of known cell wall regulatory factors, there is only one essential Serine/Threonine phosphatase- PstP in Mycobacteria, which is also itself phosphorylated by the STPKs. In this study we investigate the role of PstP in regulating the cell wall using the non-pathogenic model Mycobacterium smegmatis. We report some novel substrates of PstP in vitro, describe the significance of PstP’s phospho-sites in regulating its activity and specificity and the effects of phospho- misregulation of PstP in cell wall metabolism and antibiotic tolerance. Our findings provide substantial insights for future studies on cell wall regulation and assessing PstP as a drug target.

Keywords

Essential serine/threonine phosphatase PstP, Mycobacterial cell wall regulation

Disciplines

Biology | Life Sciences

Comments

Degree granted by The University of Texas at Arlington

Included in

Biology Commons

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