Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria

Abstract

A chemical synthesis platform with broad applications and flexibility was rationally designed to inhibit biogenesis of adhesive pili assembled by the chaperone-usher pathway in Gram-negative pathogens. The activity of a family of bicyclic 2-pyridones, termed pilicides, was evaluated in two different pilus biogenesis systems in uropathogenic Escherichia coli. Hemagglutination mediated by either type 1 or P pili, adherence to bladder cells, and biofilm formation mediated by type 1 pili were all reduced by Ϸ90% in laboratory and clinical E. coli strains. The structure of the pilicide bound to the P pilus chaperone PapD revealed that the pilicide bound to the surface of the chaperone known to interact with the usher, the outer-membrane assembly platform where pili are assembled. Point mutations in the pilicide-binding site dramatically reduced pilus formation but did not block the ability of PapD to bind subunits and mediate their folding. Surface plasmon resonance experiments confirmed that the pilicide interfered with the binding of chaperone-subunit complexes to the usher. These pilicides thus target key virulence factors in pathogenic bacteria and represent a promising proof of concept for developing drugs that function by targeting virulence factors.antimicrobials ͉ chaperone-usher pathway ͉ pilicide ͉ urinary tract infection

Molecular mechanism of bacterial type 1 and P pili assembly

“…However, there have been some successful attempts to inhibit pilus formation and these follow two main strategies, as reviewed in [66]: (i) competitive inhibition of the adhesive structures such as the mannosides [67,68] and globosides [69] and (ii) inhibition of the assembly pathway. The pilicides developed in Pinkner et al [70] and Chorell et al [71] directly target the UBS-the surface of the chaperone interacting with the NTD, where the proline lock is located. Other pillicides target the interaction between the chaperone and the subunit [72].…”

Rekurentne infekcije mokraćnih puteva: antimikrobna i imunoaktivna profilaksa

“…Pored ekstrakta brusnice ispituju se i druga antiadheziona sredstva koja se vezuju za adhezine patogenih bakterija i sprečavaju njihovu adheziju za epitelne ćelije domaćina. Novija antiadheziona sredstva su manozidi, kurlicidi i pilicidi [55][56][57].…”

Actualidades en terapéutica: nuevos antibacterianos

“…Inhibición de la adhesión: se destacan los pilicidas, éstos inhiben la formación de pilis o fimbrias, inhibiendo la plataforma acomodador, vía importante en bacterias gramnegativas [2,105].…”