Spider in the web: multiple interactions of the essential cell division protein FtsQ as novel targets for antibitotic intervention
Summary of the proposed research
The World Health Organization (WHO) has expressed serious concerns about the emergence of antimicrobial resistance along with a steady decline in the discovery of new antimicrobials. Novel antibiotics are crucial to contain and decrease the burden of infectious diseases. This AIMMS project will combine the target expertise of the Molecular Microbiology section (FALW) and the efficient drug discovery capabilities of the Medicinal Chemistry Section (FEW) to address this need.
Particularly attractive targets for antimicrobials are the many consecutive protein interactions that control bacterial cell division because they constitute a delicate process and any interference with this sequential mechanism will lead to inhibition of cell growth. The majority of interactions during cell division occur in the periplasm that is relatively accessible to small antimicrobials. Importantly, the specific process of cell division is not conserved in eukaryotic cells. Thus, inhibitors that interfere with bacterial cell division are likely to be innocuous to humans.
The division ring in Gram-negative bacteria is formed by at least ten essential proteins that assemble at midcell to effect division. We will design and explore a novel class of antimicrobials that interfere with these critical protein interactions. These interactions will be analyzed in molecular detail using various molecular approaches to detect protein interactions. This information will be used for virtual fragment screening to select compounds that are tested for decreased recruitment of relevant cell division proteins at the divisome and consequent inhibition of cell division and growth. Subsequent hit optimization will be performed using efficient fragment-based drug design, leading to tool compounds and candidate antibiotic agents.
Although the project is focused on Gram-negative bacteria, the approaches and selected compounds are likely to be relevant for Gram-positive bacteria as well, an aspect that will be explored in collaboration with the section Medical Microbiology (VUmc). An innovative element of this over-arching AIMMS project is that it is truly interdisciplinary, reflecting an established tight collaboration between the sections of Molecular Microbiology (FALW) and Medical Chemistry (FEW). Both sections have committed to fully support the proposal and use the AIMMS funding as a seed that has all the potential to grow (WHO priority diseases, neglected diseases, TI Pharma focus area, EU FP7, among others).
