Therapeutic Approaches Targeting the Assembly and Function of Chaperone-Usher Pili

Abstract

The chaperone-usher (CU) pathway is a conserved secretion system dedicated to the assembly of a superfamily of virulence-associated surface structures by a wide range of Gram-negative bacteria. Pilus biogenesis by the CU pathway requires two specialized assembly components: a dedicated periplasmic chaperone and an integral outer membrane assembly and secretion platform termed the usher. The CU pathway assembles a variety of surface fibers, ranging from thin, flexible filaments to rigid, rod-like organelles. Pili typically act as adhesins and function as virulence factors that mediate contact with host cells and colonization of host tissues. Pilus-mediated adhesion is critical for early stages of infection, allowing bacteria to establish a foothold within the host. Pili are also involved in modulation of host cell signaling pathways, bacterial invasion into host cells, and biofilm formation. Pili are critical for initiating and sustaining infection, and thus represent attractive targets for the development of anti-virulence therapeutics. Such therapeutics offer a promising alternative to broad-spectrum antibiotics and provide a means to combat antibiotic resistance and treat infection while preserving the beneficial microbiota. A number of strategies have been taken to develop anti-pilus therapeutics, including vaccines against pilus proteins, competitive inhibitors of pilus-mediated adhesion, and small molecules that disrupt pilus biogenesis. In this chapter, we provide an overview of the function and assembly of CU pili, and describe current efforts aimed at interfering with these critical virulence structures.

FimH and Anti-Adhesive Therapeutics: A Disarming Strategy Against Uropathogens

“…Then, in 1977, the anti-adhesive activity of mannose was described in detail by Ofek, Mirelman and Sharon for E. coli [19,68], and later on for other uropathogens [69][70][71]. Up until now, different categories of soluble mono-and polyvalent FimH inhibitors (α-d-mannosides, and their chemically modified derivatives and glycodendrimers, respectively) have been selected, synthesized and analyzed [17,54]. Due to the huge number of available molecules, researchers in this field established standardized protocols and techniques to test FimH inhibitory activity.…”

“…The three most common uropathogenic pathogens, UPEC, UPKP and UPPM, are armed by adhesive pili or fimbriae, mostly belonging to the Chaperone-usher (CU) pathway [ 5 , 12 ]. The axial and pivotal role of these important virulence factors in bacterial pathogenicity and virulence has sped up the development of anti-fimbrial therapeutic approaches [ 17 ]. Among these new approaches, the anti-adhesive strategy seems an effective and valid treatment procedure for UTIs.…”

Identification and evaluation of novel vaccine candidates against Shigella flexneri through reverse vaccinology approach

“…5 The workflow of selection and experimental confirmation of selected vaccine candidate (FimG). At the end of the process, the vaccine candidate was verified as a potent vaccine candidate and therefore supports reverse vaccinology approach as an effective method for the development of new vaccines appropriate vaccine targets (Psonis and Thanassi 2019). For instance, FimA and FimH have been employed for vaccine development in E. coli (Asadi Karam et al 2013;Ma et al 2018;Pore and Chakrabarti 2013).…”

Processive Dynamics of the Usher Assembly Platform During UropathogenicEscherichia coliP Pilus Biogenesis

“…Given their central roles in initiating and sustaining infection, there is intense interest in understanding the molecular mechanisms of pilus assembly and function. Such knowledge may facilitate the development of pilus-targeted therapeutics as an alternative or complement to traditional antibiotics 6,7 .…”