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The role of FK506 Binding Proteins in the virulence of Neisseria meningitidis

Kibble, Emily A. (2021) The role of FK506 Binding Proteins in the virulence of Neisseria meningitidis. PhD thesis, Murdoch University.

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Embargoed until November 2023.

Abstract

FK506 Binding Proteins (FKBPs) are a subfamily of the immunophilin protein superfamily which all exhibit peptidyl-prolyl cis-trans isomerase (PPIase) activity and are important for protein folding. The FKBP subfamily consists of the highly conserved Macrophage Infectivity Potentiator (Mip) and Mip-like proteins, Trigger factor and “sensitive to lysis D” (SlyD) proteins, which are known to be important for virulence in many bacterial species. Consequently, FKBPs are attractive targets for the generation of broad spectrum antivirulence therapeutics. The aim of this study was to investigate the role of FKBPs in Neisseria meningitidis, the bacterial causative agent of invasive meningococcal disease (IMD).

N. meningitidis encodes for four FKBPs: Mip-like proteins NEIS1487 (mip1) and NEIS0004 (mip2), NEIS1250 (tig) and NEIS1451 (slyD). Four N. meningitidis deletion mutant strains were created and characterised: single deletion mutants NMBΔmip1, NMBΔmip2, and NMBΔtig, and double deletion mutant NMBΔmip1Δmip2. NMBΔmip1 and NMBΔmip2 displayed reduced virulence, including decreased survival in human serum and in macrophages, with this phenotype being exaggerated in the double deletion mutant NMBΔmip1Δmip2. Differences in other phenotypes exhibited between NMBΔmip1 (increased biofilm production) and NMBΔmip2 (growth defect at suboptimal temperature), indicates that the two Mip-like proteins have distinct roles within N. meningitidis. NMBΔtig displayed different virulence-associated phenotypes, including increased capsule and biofilm production. Recombinant NmMip1, NmMip2 and NmTig were found to be active PPIases, inhibitable by rapamycin, the natural inhibitor of FKBPs. Furthermore, novel small molecule compounds based on the structure of rapamycin were screened against N. meningitidis. These compounds inhibited the PPIase activity of recombinant NmMip1 and NmMip2 and significantly reduced intracellular survival of N. meningitidis.

This study has shown that FKBPs NmMip1, NmMip2 and NmTig are enzymatically active proteins which each play significant roles in the virulence of N. meningitidis. In particular, the Mip-like proteins of N. meningitidis are key druggable targets for novel anti virulence therapeutics.

Item Type: Thesis (PhD)
Murdoch Affiliation(s): Medical, Molecular and Forensic Sciences
Supervisor(s): Sarkar-Tyson, Mitali, Kahler, Charlene and Coombs, Geoffrey
URI: http://researchrepository.murdoch.edu.au/id/eprint/62887
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