Characterization of cell elongation and chromosome segregation determinants in mycobacteria
Date
2020
Authors
Mdlalose, Noluthando Magugu
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Abstract
Tuberculosis (TB) continues to lay a heavy burden on public health systems worldwide and is
one of the leading causes of death from a single infectious agent, namely Mycobacterium
tuberculosis (Mtb). The burden of TB is not only represented by the current active disease cases,
which are associated with a high mortality rate but also the ongoing threat of latent TB infection,
which further exacerbates the epidemic. The emergence of multi-drug resistant strains created an
urgent need for the identification and investigation of more effective therapeutics with less
toxicity that can potentially reduce the treatment period and eventually eliminate this disease. In
this context, the mycobacterial cell wall, which is a complex multi-layered envelope, assembled
at the cell poles, represents an ideal area for the discovery of new drugs. The biosynthesis of this
macromolecule is coordinated by the enzymatic addition of chemically diverse cell wall layers.
The enzymes which regulate the cytosolic layers of peptidoglycan (PG), arabinogalactan (AR)
and mycolic acid (MA) synthesis are localized at cell growth and division sites. These enzymes
have to be carefully regulated to maintain cell wall homeostasis and any disturbances will affect
cell survival, thus making the process of cell wall assembly vulnerable for drug development.
The mycobacterial PG layer has been identified as being a crucial component of cell wall
integrity. The remodeling of PG is facilitated by several enzymes including penicillin-binding
proteins (PBPs), which carry out their function through interacting with partnering proteins. This
study was focused on identifying the interacting partners of Wag31/DivIVA, an important cell
division protein that is localized at the poles and facilitates the recruitment of other cell division
proteins. Interacting partnering proteins were identified through a mycobacterial protein
complementation assay (M-PFC). The screen identified five novel different interaction partners.
Three of these possibly contribute to chromosome segregation (RecR) and cellular processes
including cell division (UvrABC transporter and Cys proteins). DivIVA proteins have been
demonstrated to interact with a great variety of proteins in other species, from transmembrane to
cytosolic proteins. This ability to interact is attributed to the highly conserved amphiphilic
domains. These new partners provide additional information on how DivIVA coordinates
cellular growth and also identifies new proteins that can serve as potentially important drug
targets
Description
A dissertation submitted in fulfilment of the requirements for the degree of Master of Science in Medicine to the Faculty of Health Sciences, School of Pathology, University of the Witwatersrand, Johannesburg, 2020