Abstract
Mycobacterium abscessus is a non-tuberculous mycobacterium responsible for severe and chronic infections, especially in cystic fibrosis patients. This bacterium is naturally resistant to most commonly used antibiotics, rendering treatments very challenging and often leading to therapeutic failure. Therefore, there is an urgent need for the discovery of new chemical entities and effective therapies to fight against M. abscessus. In this context, this study aimed at identifying new compounds and therapeutic combinations active against M. abscessus. A first approach consisted in characterizing new benzimidazole derivatives displaying high activity in vitro, in cellulo and in vivo against M. abscessus. MmpL3, the mycolic acid transporter, was identified as the primary target of these compounds. A second approach focused on the repurposing of existing antibiotics, as highlighted by the efficacy of bedaquiline in a new murine model of persistent infection. Furthermore, we demonstrated that rifabutin, another repurposed drug candidate, is active against both the intracellular and extracellular forms of M. abscessus. A third axis of this work was dedicated to identify possible synergistic drug combinations, allowing to use lower drug concentrations required to achieve the same or greater effect than with drugs used separately. To this end, we showed the synergistic effects between MmpL3 inhibitors and β-lactams (imipenem and cefoxitin). Other molecules, lacking anti-microbial activity, can also be used to potentiate the activity of antibiotics, as demonstrated with verapamil, which enhances the efficacy of bedaquiline in vitro and in macrophages. Collectively, these results open the door to new therapeutic perspectives against M. abscessus pulmonary diseases.