Dynamic studies to facilitate design of new anti virulence compounds targeting the Chaperone Usher Pathway in E. coli

SNIC 2019/3-526


SNIC Medium Compute

Principal Investigator:

Fredrik Almqvist


UmeƄ universitet

Start Date:


End Date:


Primary Classification:

30103: Medicinal Chemistry

Secondary Classification:

10405: Organic Chemistry

Tertiary Classification:

10499: Other Chemistry Topics




The increasing problem of bacterial resistance towards antibiotics demand new strategies in drug design. The design of drugs that target bacterial virulence, rather than killing the bacteria, is one such promising strategy that would decrease the pressure for development of resistance. We have previously identified compounds based on ring-fused 2-pyridones that target bacterial virulence by inhibiting the assembly of pili for E. coli. Pili are essential for attachment of the bacteria to the host. The assembly of P-pili is directed by the PapC usher, from different subunits delivered as complexes with PapD. X-ray crystal structures have revealed that the ring-fused 2-pyridone compounds disrupt the interactions between PapD and the NTD domain of the PapC usher, thus inhibiting pili formation. MD simulations will be performed for 2-pyridones in complex with PapD to aid in the design of more potent compounds, prior to synthesis. Interactions between NTD and the CTD2 domain of the PapC usher also plays a critical role during the pilus assembly. A new project focus on the design of compounds binding to the cleft of CTD2 that interacts with NTD, with the aim to block these essential interactions at the Usher.(1) A virtual screen has been performed to identify promising compounds that will be used as starting points for this project. MD simulations of a selection of these compounds in complex with CTD2 will be performed to further validate their potential as inhibitors of pili formation, prior to synthesis and ordering of commercial compounds that will then be biologically evaluated. (1) Omattage, N. S.; et. al. Structural basis for usher activation and intramolecular subunit transfer in P pilus biogenesis in Escherichia coli, Nature Microbiology, 2018 in press, DOI: 10.1038/s41564-018-0255-y.