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Title: The role of the N-glycolyl modification in Mycobacterial peptidoglycan synthesis and survival
Author: McFeely, Daniel
ISNI:       0000 0004 9350 7838
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2019
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Mycobacteria are acid fast bacilli responsible for the wide spread global diseases tuberculosis and leprosy. The increased persistence of multidrug resistant (MDR) mycobacterial strains has led to the focus on discovery of new and under-utilised cellular targets such as the cell wall. Peptidoglycan, the principle structural component of the bacterial cell wall is a heteropolymer comprised of alternating monosaccharides cross-linked by pentapeptide chains. The cell wall of mycobacteria are inherently resistant to antimicrobials and aid in evasion from host immune detection due to modifications to its composition. The hydroxylase enzyme NamH has been documented to play a role in the N-glycolylation of peptidoglycan monosaccharides, utilizing molecular oxygen during aerobic growth to convert N-acetylto N-glycolyl groups. This modification is found predominantly in Actinobacteria, except Mycobacterium leprae due to genomic reduction. The percentage incorporation of Nacetylated and N-glycolylated saccharides is dependent upon the environment and functional characterisation of the impact of each modification is vital to achieving a greater understanding into mycobacterial response to a range of factors including dormancy, resuscitation and intracellular propagation. The investigations described in this thesis concern the susceptibility of a M. smegmatis DnamH strain, the cell wall of which contains solely N-acetylated cell wall components towards: (a) selected hydrolytic enzymes, as a model of the survival of phagocytosed mycobacteria within the harsh conditions of the phagolysosome and; (b) new and existing antimicrobials commonly used as therapies against infection. The absence of the Nglycolylated sugar within the peptidoglycan cell wall led to consistently observed increases in susceptibility to a range of hydrolytic enzymes and antimicrobials, especially those which target the formation of peptidoglycan. Mycobacterial Mur ligases demonstrated increased catalytic bias towards N-glycolylated substrates to increase their inclusion into the wide peptidoglycan sacculus. Investigations were expanded to characterize the impact of newly discovered known cell wall active compounds against the peptidoglycan biosynthesis machinery.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry ; QP Physiology ; QR Microbiology ; RC Internal medicine