Researchers in Prof. Scott Hultgren’s laboratory have discovered an antibiotic-sparing method for treating infections from E. coli and other Gram-negative bacteria. This approach is designed to block pathogens from colonizing their host by using small molecule inhibitors of the chaperone-usher pathway for pilus assembly.
Gram-negative pathogens, such as those that cause urinary tract infections, have hair-like adhesive fibers (pili) that assemble on their surface. These pili mediate microbial attachment and are critical for host-pathogen interactions. Therefore, bacterial pathogenicity can be diminished by preventing the pilus assembly. This technology provides a molecular snapshot that elucidates the specific interface where pilus assembly can be blocked by small molecule called pilicides. Revealing this mode of action lays the ground for the future structure-activity-relationship studies that are necessary to develop even more potent inhibitors for novel antibacterial therapies.
Schematic of pilus assembly: red star indicates structural target for small molecule inhibitors
Stage of Research
The inventors solved the first full-length crystal structure of an usher molecule in the process of being activated to assemble pili. This structure revealed a specific interface where pilicides (small molecular weight inhibitors of pilus assembly) bind.
- Drug development for antibacterial agents – identify small molecule compounds to prevent infection from and attenuate virulence in Gram-negative bacteria (for example, agents to treat urinary tract infections (UTIs) caused by E. coli)
- Antibiotic-sparing – pilicides offer an alternative to traditional antibiotics:
- could be effective against antibiotic resistant strains
- expected to be minimally disruptive to good bacteria
Publications – Omattage, N. S., Deng, Z., Pinkner, J. S., Dodson, K. W., Almqvist, F., Yuan, P., & Hultgren, S. J. (2018). Structural basis for usher activation and intramolecular subunit transfer in P pilus biogenesis in Escherichia coli. Nature microbiology, 3(12), 1362-1368.
Patents – Patent application pending