Convergent medicinal chemistry approaches against susceptible and resistant mycobacterial infections

Mycobacterial infections are a group of multisystem diseases caused by the organisms of the family Mycobacteriaceae, such as Mycobacterium tuberculosis complex, Mycobacterium leprae and Nontuberculous mycobacteria (NTM). Among those, tuberculosis remains one of the top 10 causes of death worldwide and the increasing emergence of resistance further worsen an already threatening scenario. In spite of this, first-line drugs used for susceptible TB were developed more than half a century ago, and most of the clinical studies defining their optimal combination were completed in the 1970s, highlighting a cogent need for pursuing innovative drug discovery programs. Although the development of drugs targeting novel biochemical pathways remains a valuable approach it is incomplete and the lack of innovation in the discovery approach and/or in the combination of the therapeutic cocktail makes quite predictable the onset of resistance also for the newly marketed drugs. Recently, interest of researchers has been caught by the potential use of adjuvant molecules, which are non-bactericidal agents able to boost the effect of antibacterials by targeting virulence factors or helping the immune system in clearing the infection. Among the adjuvants, those inhibiting the efflux pumps have shown promising results both in vivo and in vitro. In this work, three convergent approaches were considered to provide novel therapeutic options for the treatment of TB. From one hand, starting from promising hit compounds, a hit-to-lead optimization study was successfully carried out defining a panel of structure-activity relationships and structure-metabolism relationships useful for further development. On the other hand, attempts to synthesize potent and not cytotoxic mycobacterial efflux pump inhibitors were made through a ligand-based drug design approach starting from an in-house hit. Finally, the possibility to exploit protein degradation as a target for therapeutic intervention was evaluated through the synthesis of small-peptide inhibitors of Pup/PafA interaction.