Ironing out Fe3+ acquisition in M. abscessus: a new strategy to target virulence factors in non-tuberculous mycobacteria

M. abscessus (Mab), which belongs to the class of non-tuberculous mycobacteria (NTM), is an opportunistic pathogen that causes chronic pulmonary infections in sensitive individuals, especially cystic fibrosis (CF) patients. Due to the intrinsic resilience of NTM to the available treatments, which is worsened by the dramatic spread of resistant strains, new therapeutic strategies are urgently needed. In this context, iron acquisition has recently emerged as an interesting target in the phylogenetically close M. tuberculosis (Mtb), due to the involvement of this metal in the pathogenesis and survival of the microorganism in the host. Hence, we investigated the targeting of mycobacterium-specific iron chelators as a possible anti-virulence approach against Mab. In detail, we focused on the first enzyme involved in the siderophore biosynthetic pathway, a salicylate synthase (SaS) that has been successfully studied to identify antitubercular agents against Mtb. Due to the structural conservation of the active site in the two congeners, we approached this study by screening an in-house library of Mtb-SaS inhibitors. This initial investigation led to the identification of the first hit compounds against Mab-SaS. Their activity was rationalized using a homology model, based on the PDB coordinates of the Mtb protein. However, considering the high plasticity of the active site and the flexibility of two loops adjacent to the binding cavity, we decided to perform crystallization studies to solve the structure of Mab-SaS, thus providing a solid base to structure-based drug design efforts. The obtaining of the first 3D-model of this enzyme allowed us to characterize its orthosteric site and study the peculiar area around it. Our preliminary but promising results will be presented, along with perspectives on the use of the new structure for the development of optimized inhibitors.