University College London
Chemistry

In 2020, COVID-19 caused massive suffering with no cure. While the pandemic seems behind us, optimism following penicillin’s discovery previously led many to believe the fight against infections was over. Antimicrobial resistance (AMR) occurs when drugs fail against microorganisms, making infections harder to treat. This crisis highlights an urgent need for new antimicrobials with novel targets.

Traditionally, antimicrobial drug discovery relies on screening massive collections of millions of non-covalent small-molecules to identify new drugs. Despite this, extensive screenings have yielded no new antibiotic class since 1987, revealing the approach's limitations. In recent decades, cyclic peptides (CPs) have gained attention for their stability, target-specificity, and ability to bind challenging targets that small-molecules cannot. Daptomycin, a non-covalent CP, was approved for bacterial infections, showcasing the medicinal value of CPs. Driven by advances in molecular biology, large collections of CPs can now be efficiently prepared. While most research focuses on non-covalent CPs, I aim to explore their covalent counterparts. Like penicillin, covalent drugs engage their targets irreversibly, often offering greater potency. I believe covalent CPs, combining the benefits of both strategies, hold significant antimicrobial potential.

While approaches for screening mixtures of covalent CPs have been reported, they are typically unsuitable for discovering antimicrobials because they rely on 'tags' attached to individual CPs for technical reasons. Thus, these 'tagged mixtures' can only be screened on target proteins, not on microbes. Consequently, strong enzyme inhibitors identified from these tagged mixtures often fail to show activity against microbes due to poor cellular uptake. In this fellowship, I will develop ‘tag-free mixtures’ of covalent CPs and screen them directly on microbes to identify CPs that kill them. Their modes of action will be investigated through proteomic, genetic, and biochemical studies. My ultimate goals are to discover novel targets and establish covalent CPs as a new antimicrobial class.