Mycobacterium abscessus siderophores biosynthesis as a target to inhibit the iron uptake mechanism

Mycobacterium abscessus (Mab) is a rapid-growing non-tuberculous mycobacterium, which is emerging as an opportunistic pathogen in patients with lung disorders, such as those with cystic fibrosis. With the aim of searching for new anti-virulence treatments, which do not kill the bacteria but disarm them before attacking the host, we focused on the siderophores biosynthesis. Mab produces siderophores to scavenge iron from the host, that are essential for the establishment and maintenance of infection. The salicylate synthase (Mab-SaS), the first enzyme involved in the biosynthesis of siderophores, catalyses the conversion of chorismate into salicylic acid. Its homologue in M. tuberculosis (Mtb-MbtI) has already been extensively characterised and identified as a promising therapeutic target, and promising phenylfuran-carboxylate based inhibitors were developed. Taking into consideration the successful work performed on M. tuberculosis, the aim of this work is therefore to identify compounds capable of inhibiting the enzymatic activity of the Mab-SaS, starting from the library of compounds developed for Mtb-MbtI. The Mab-SaS was then produced in recombinant form, and its enzymatic activity established by a fluorimetric assay. Upon screening of the compounds belonging to the library of Mtb-MbtI inhibitors, some showed good activity even against Mab-SaS, with IC50 values in the low micromolar range, and not behaving as PAINs. These results support the hypothesis that phenylfuran-carboxylate is a promising scaffold for the inhibition of Mab-SaS as well, paving the way for the optimization and rational design of more potent derivatives.