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Title: Host-pathogen-drug interactions in the context of antibiotic resistance : how host xenobiotic metabolism can affect antibiotic efficacy in a Methicillin-Resistant Staphylococcus aureus infection
Author: Tonneau, C.
ISNI:       0000 0004 7969 573X
Awarding Body: University of Exeter
Current Institution: University of Exeter
Date of Award: 2019
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Our arsenal of weapons to fight against bacterial infections is weakening: bacteria are gaining resistance to the common antibiotics, while industries are struggling to develop new effective ones. To avoid triggering de-novo antibiotic resistance, we need the right antibiotic for the specific bacteria, at a dose adapted to the patient genetics. Genes driving the degradation of antibiotics have indeed known genetic variants that can dramatically affect the kinetics of antibiotic metabolism from one patient to another. This could lead to treatment failure, excessive side effects or emergence of resistance. I first investigated the clinical relevance of the vancomycin-rifampicin combination to treat Methicillin-Resistant Staphylococcus aureus infections (Chapter 3). I showed in various experimental settings that these two antibiotics may promote an environment prone for antibiotic resistance. Their interaction might be unstable in vitro because of environmental factors, one could wonder how the host environment might generate such instability. I then explored how interactions between antibiotics and host xenobiotic genetics could influence antibiotic concentrations, potentially triggering increased treatment failure, side-effects and antibiotic resistance in patients carrying particular variants. In silico, I estimated the effects of genetic variants of the Cytochrome P450 3A4 gene to its enzyme, and, as they are unequally distributed in the world, their global relevance (Chapter 4). In vivo, I focused on the Carboxylesterase 2 gene and I found two of its variants, rs11075646 and rs8192925, capable of significantly altering the degradation of various drugs, including rifampicin and mycophenolate mofetil. A clinical study was designed, to explore possible correlations between genotype for these variants and treatment response in patients (Chapter 5). Altogether, this body of work highlights the prescribing importance of considering not only the strain in bacterial infections, but also the genetics of the human host. This raises a need to make sure the right antibiotics are used in practices, at doses adapted to the patients. As part of personalised medicine, checking their genotype for these biomarkers could tailor their therapy, improving recovery while avoiding antibiotic resistance.
Supervisor: Beardmore, R. ; Harries, L. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: antibiotic resistance ; Staphylococcus aureus ; Methicillin-Resistant Staphylococcus aureus ; MRSA ; antibiotic ; combination ; vancomycin ; rifampicin ; antagonism ; synergy ; xenobiotic metabolism ; cytochrome ; P450 ; CYP3A4 ; Carboxylesterase 2 ; CES2 ; polymorphism ; genetic variant ; Single Nucleotide Polymorphism ; SNP ; rs11075646 ; rs8192925 ; side-effects ; mycophenolate mofetil ; personalised medicine ; tailored therapy