Mycobacterium abscessus (Mab) can cause severe infections in people with cystic fibrosis and is resistant to many drugs, so new strategies are needed to fight it. 
One promising approach is anti-virulence therapy, which is the use of compounds that do not kill the pathogens, but prevent them from attacking the host, reducing the development of drug resistance. 
The acquisition of iron is crucial for the growth and virulence of Mab: this is achieved by molecules produced by the bacterium called siderophores. The project aimed to develop iron uptake inhibitors in Mycobacterium abscessus targeting siderophores.

The researchers produced Mab’s enzyme salicylate synthase (SaS), which is responsible for the first step in the production of siderophores, to screen and develop molecules capable of inhibiting the synthesis of siderophores through in vitro assays and computer modelling and simulation methods (in silico).
First, the three-dimensional structure of SaS was studied, whereby thousands of molecules were screened in silico to identify the chemical structures that could best bind to the enzyme and interfere with its activity. 
The structure of the bacterial SaS enzyme was elucidated and this enabled the identification, by means of virtual simulations, of different compounds, belonging to different chemical classes, capable of inactivating the enzyme. 

Then, the researchers synthesised the best molecules and evaluated their activity using biochemical and biophysical methods, and the most effective molecules were evaluated for their ability to interfere with iron metabolism in mycobacteria.
Some of these molecules showed the ability to interfere with iron supply in in vitro cultures of mycobacteria.

This project led to the identification of molecules that interfere with the iron uptake mechanisms of Mab, laying the foundations for the development of a new anti-virulence strategy. The best ones will now undergo optimisation processes to improve their activity.