iSonitriles: innovative pHarmacOphoric GroUps as aNtibacterial agents against multidrug resistance pathogenic bacteria (SHOGUN)

Antimicrobial resistance is a growing concern worldwide and could trigger the next global pandemic. Nowadays, with the available arsenal of antibacterial agents, it is increasingly difficult to treat infectious diseases that were considered common and curable in the second half of the 20th century. Even worse, for some pathogens there are no treatment options left, leading to a steady increase in the number of deaths. To overcome this threat, innovative concepts are required to kill bacteria via unprecedented mechanisms of action. The main objective of this proposal is to use the isonitrile functional group as warhead moiety in the design of innovative antibacterial agents. So far, isonitriles have been considered highly reactive and metabolically unstable compounds, and this idea has prevented their use in drug discovery. However, mounting evidence are showing peculiar properties for the isonitrile functional group suggesting applications in medicinal chemistry as metalloenzymes inhibitor. Indeed, due to the well-known coordinating ability with transition metals such as zinc, copper, and iron (to cite those most important in living cells) isonitriles can act as warheads for the inhibition of metalloenzymes from bacteria, fungi, and protozoa. The consortium involves a team of medicinal chemists, microbiologist and analytical chemists located in Novara (UPO) and Verona (UNIVR) that will share their complementary expertise to deeply explore the potential of isonitrile-containing molecules as novel antibacterial agents. The SHOGUN project will be organized in four thematic work packages. The first one (WP1) consists in the design and synthesis of isonitrile-containing compounds as putative antibacterial agents. These compounds will be synthesized using traditional approaches as well as by adopting innovative methods including multicomponent reactions, electrochemistry and click chemistry to overcome limitations of conventional synthesis and speed up compounds’ throughput. In the WP2, all the synthesized compounds will be evaluated for their antibacterial activity, and inhibition of biofilm formation. In the WP3 ADME properties of the most promising compounds will be evaluated. According to the data obtained in the WP2 and WP3, further molecules will be synthesized in WP1 to improve their pharmacokinetic and pharmacodynamic properties. The WP4 will be focused on the identification of the mechanism of action of the novel synthesized isonitriles which have shown to be potent antibacterial agents. Analytical and proteomic techniques will be used to fulfill this task. The final goal of this research will be the identification and selection of 2-3 lead candidates to enable future preclinical and clinical investigations.