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Title: Tackling Mycobacterium abscessus infection in Cystic Fibrosis
Author: Rodriguez Rincon, Daniela
ISNI:       0000 0004 7229 2890
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
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Mycobacterium abscessus is an emerging pathogen with infections increasing worldwide, especially among Cystic Fibrosis (CF) patients. During my PhD, I studied key aspects of the biology of M. abscessus spp.; particularly, I studied host-pathogen interactions, antimicrobial resistance mechanisms, and genetic determinants of virulence. First, I performed phenotypic characterization of M. abscessus spp. clinical isolates obtained from CF patients classified according to subspecies and clustering. I found clustered isolates, representing probable transmission events, were phenotypically distinct from sporadic isolates and showed adaptation phenotypes associated with chronic lung infection, such as enhanced intracellular survival, increased antibiotic resistance, and metabolic adaptations to the host environment. Second, I assessed the role of an inserted element containing an active methyltransferase in M. a. massiliense. Infection experiments with an isolate containing the inserted element (BIR1049wt) and a knockout strain (BIR1049Δ1809078_1815649) showed decreased survival of BIR1049Δ1809078_1815649 within macrophages. RNAseq analysis showed a distinct gene expression pattern between both isolates, with a number of mycobacterial virulence factors upregulated in BIR1049wt. Third, I studied heritable non-mutational antibiotic resistance mechanisms in M. abscessus to linezolid and clofazimine. For both antibiotics, I found clonal isolates of M. abscessus spp. with varying susceptibilities and different gene expression patterns, suggesting transcriptional regulation of antibiotic resistance. Mutation- mediated resistance to clofazimine was also found due to mutations in two transcriptional regulators predicted to regulate efflux pumps. Last, I evaluated the potential of repurposing a kinase inhibitor (compound H) in clinical trials for the treatment of cancer and CF, to treat M. abscessus infection. I found compound H enhanced killing of intracellular M. abscessus in macrophages through stimulation of autophagy and lysosomal function. I further studied over 60 chemical analogues of compound H in order to find a more active and specific compound for M. abscessus infection.
Supervisor: Floto, Rodrigo Andres Sponsor: CF Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Mycobacterium ; abscessus ; infection ; cystic ; fibrosis