Investigating Mycobacterium abscessus to inform treatment and drug discovery

Abstract

The environmental non-tuberculous mycobacteria, Mycobacterium abscessus, is quickly becoming a major health concern in developed countries in part to its extensive multi-drug resistance. Those at risk of contracting M. abscessus lung disease are primarily people who are immunocompromised or have pre-existing lung disorders such as Cystic Fibrosis. Treatment for this disease involves a lengthy regimen of several antibiotics, despite this, treatment failure rates remain unacceptably high. The background of this infectious disease, its clinical manifestation and management is discussed in detail in Chapter 1. The first results chapter of this thesis, chapter 2, makes use of genomic techniques to explore the subspecies of a panel of M. abscessus clinical isolates, alongside their drug susceptibility patterns, in order to elucidate a link between M. abscessus subspecies (M. abscessus subsp. abscessus, M. abscessus subsp. bolletii, and M. abscessus subsp. massiliense) and drug resistance. Given the high levels of treatment failure, it is essential to find new treatments for M. abscessus infections, that can be introduced into clinical practice in the near future. Chapter 3 of this thesis explores the repurposing of a new and approved β-lactamase inhibitor, relebactam, for inclusion into the M. abscessus chemotherapeutic regimen. Here, relebactam’s efficacy against the endogenous M. abscessus β-lactamase, BlaMab is discovered, as well as its inhibitory activity when combined with the carbapenem, imipenem. This activity is further potentiated with by the addition of amoxicillin. This three-drug combination has widespread activity against a panel of clinical isolates, within a therapeutically achievable concentration range. Finally, an in vitro model of persistence in M. abscessus infection was developed and this was used to assess frontline drug susceptibilities, providing an insight into the possible causes of treatment failure for this infection. Overall, this body of work contributes to the knowledge of the organism, provides a greater understanding of the clinical challenge it represents and proposes a new treatment option for patients suffering with this deadly infection.