CsgA (microbial amyloid)

Class

gut-selective small molecule

CsgA is the major protein subunit of curli, extracellular fibers produced by certain gut bacteria, including strains of Escherichia coli. Curli belong to a class of "functional amyloids" - proteins that adopt the same cross-beta sheet architecture found in disease-associated amyloids, but that bacteria assemble deliberately as part of normal physiology rather than as a pathological byproduct. Curli fibers allow bacteria to adhere to surfaces and to one another, forming the structural scaffold of biofilms, and they also engage host immune receptors. Because biofilms shield bacteria from antibiotics, host defenses, and mechanical clearance, blocking curli assembly is being explored as a way to disrupt bacterial colonization without necessarily killing the organism - an antivirulence strategy that may reduce selective pressure for antibiotic resistance. Separately, curli's amyloid fold has drawn interest because it can template misfolding of host proteins; gut-derived curli exposure has been linked in research to aggregation of alpha-synuclein, the protein implicated in Parkinson's disease, motivating interest in this pathway for gut-brain axis biology. A gut-selective small molecule directed at CsgA is designed to act within the intestinal lumen, limiting systemic absorption while addressing curli's role in local colonization and its downstream consequences.