New strategies to eradicate microbial resistance

Abstract

Antibiotics have always been considered one of the most relevant discoveries of the 20th century. Unfortunately, the dawn of the antibiotic era has sadly corresponded to the raise of the phenomenon of antimicrobial resistance (AMR), which is a natural process whereby microbes evolve in such a way to withstand the action of drugs. In this context, the identification of new potential antimicrobial targets and/or the identification of new chemical entities as antimicrobial drugs are of great demand. Among the many possible approaches used to identified novel tools to study and possibly tackle down bacterial infections, my research activity mainly focused on: (i) synthesis of potential inhibitors of microbial targets, which are involved in microbial population growth during infection; and (ii) modifications of the scaffold of natural products endowed with antimicrobial activity. The Sulfur Assimilation Pathway (RSAP) and the Carbonic Anhydrase (CA) have been investigated since their involvement in relevant phases of the bacterial life cycle. In both cases promising results were obtained, with the identification of low-nanomolar and -micromolar inhibitors for RSAP and CA enzymes, respectively. Moreover, we reported the structural modification of a secondary metabolite of Fungi, namely Brefeldin A (BFA), which is endowed with interesting biological activities, including antimicrobial effects. Our synthetic strategy allows us to obtain different C-13 BFA-derivatives in just one step, with the desired stereochemistry for all the 5 stereocenters. The compounds obtained will be tested as antimicrobial agents so as to perform preliminary SAR studies. Finally, during the course of my PhD, I have worked, for four months, at the Institute of Pharmaceutical Sciences – ETH Zürich, in the laboratory of Prof. Dario Neri and my work was focused on: hit validation in DNA-encoded chemical library (DECLs). Such technology can be applied for the identification of new antimicrobial compound for unexplored targets.