Abstract
The abundance of therapeutic failures encountered with the opportunistic pathogen Mycobacterium abscessus justifies the crucial need to diversify available treatments in order to eradicate these infections. Phage therapy combined with antibiotherapy offers a promising therapeutic alternative to cystic fibrosis patients infected with multidrug-resistant M. abscessus. However, the ability of M. abscessus to spontaneously resist therapeutic mycobacteriophages could hamper treatment efficacy. During phage infection, the lipid-rich mycobacterial cell wall provides the bacterium a plethora of targets that can be modified to inhibit the phage cycle. In this context, this thesis work aimed to evaluate the role of surfaceexposed lipids, trehalose polyphleates (TPP) and glycopeptidolipids (GPL), in the interactions between mycobacteriophages and M. abscessus. By screening a transposon library, this work has demonstrated, for the first time, the use of a co-receptor (TPP) by therapeutic mycobacteriophages. This co-receptor is proposed to facilitate access to their primary receptor which is not yet known and potentially essential. In addition, the ability of these phages to evolve for retaining their lytic efficacy against TPP-deficient strains has enabled to broaden the spectrum of action for mycobacteriophages currently available to clinicians. At the same time, the discovery of the first lytic phage specific to smooth strains and adhering to the bacteria via a process probably involving GPL, the lipids characteristic of this variant, could considerably contribute to expand the existing therapeutic phage arsenal. Thanks to the construction of mutants with truncated GPL variants, our work has revealed a role for the carbohydrate motifs of GPL in phage interactions. However, acetylation of the carbohydrate motif, governed by four acetyltransferases, including one produced by a prophage in M. abscessus, has no impact on phage efficacy. In conclusion, this thesis work has increased knowledge of the early stages of mycobacterial infection by mycobacteriophages, while broadening the range of available therapeutic phages. In addition to this work, future studies will investigate the mechanisms of mycobacteriophage resistance in M. abscessus, and thus contribute to the development of new phage cocktails while limiting the emergence of resistant strains.