Design and Synthesis of C-2 Substituted Thiazolo and Dihydrothiazolo Ring-fused 2-pyridones: Pilicides with Increased Antivirulence Activity

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2010 Jul 1

PMID 20586493

Citations 40

Authors

Erik Chorell

Jerome S Pinkner

Gilles Phan

Sofie Edvinsson

Floris Buelens

Han Remaut

Gabriel Waksman

Scott J Hultgren

Fredrik Almqvist

Affiliations

Soon will be listed here.

Abstract

Pilicides block pili formation by binding to pilus chaperones and blocking their function in the chaperone/usher pathway in E. coli. Various C-2 substituents were introduced on the pilicide scaffold by design and synthetic method developments. Experimental evaluation showed that proper substitution of this position affected the biological activity of the compound. Aryl substituents resulted in pilicides with significantly increased potencies as measured in pili-dependent biofilm and hemagglutination assays. The structural basis of the PapD chaperone-pilicide interactions was determined by X-ray crystallography.

Citing Articles

Beyond Antibiotics: What the Future Holds.

Benyamini P Antibiotics (Basel). 2024; 13(10).

PMID: 39452186 PMC: 11504868. DOI: 10.3390/antibiotics13100919.

Beyond antibiotics: CRISPR/Cas9 triumph over biofilm-associated antibiotic resistance infections.

Zuberi A, Ahmad N, Ahmad H, Saeed M, Ahmad I Front Cell Infect Microbiol. 2024; 14:1408569.

PMID: 39035353 PMC: 11257871. DOI: 10.3389/fcimb.2024.1408569.

Inducing vulnerability to InhA inhibition restores isoniazid susceptibility in drug-resistant .

Harrison G, Wang E, Cho K, Mreyoud Y, Sarkar S, Almqvist F mBio. 2024; 15(3):e0296823.

PMID: 38294237 PMC: 10936210. DOI: 10.1128/mbio.02968-23.

Biofilm and wound healing: from bench to bedside.

Goswami A, Basu S, Banerjee T, Shukla V Eur J Med Res. 2023; 28(1):157.

PMID: 37098583 PMC: 10127443. DOI: 10.1186/s40001-023-01121-7.

Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics.

Nye T, Tukenmez H, Singh P, Flores-Mireles A, Obernuefemann C, Pinkner J Proc Natl Acad Sci U S A. 2022; 119(43):e2210912119.

PMID: 36252016 PMC: 9618150. DOI: 10.1073/pnas.2210912119.

References

Sauer F, Pinkner J, Waksman G, Hultgren S . Chaperone priming of pilus subunits facilitates a topological transition that drives fiber formation. Cell. 2002; 111(4):543-51. DOI: 10.1016/s0092-8674(02)01050-4. View

Cusumano C, Hultgren S . Bacterial adhesion--a source of alternate antibiotic targets. IDrugs. 2009; 12(11):699-705. View

Bann J, Pinkner J, Frieden C, Hultgren S . Catalysis of protein folding by chaperones in pathogenic bacteria. Proc Natl Acad Sci U S A. 2004; 101(50):17389-93. PMC: 536034. DOI: 10.1073/pnas.0408072101. View

Aberg V, Hedenstrom M, Pinkner J, Hultgren S, Almqvist F . C-Terminal properties are important for ring-fused 2-pyridones that interfere with the chaperone function in uropathogenic E. coli. Org Biomol Chem. 2005; 3(21):3886-92. DOI: 10.1039/b509376g. View

Remaut H, Tang C, Henderson N, Pinkner J, Wang T, Hultgren S . Fiber formation across the bacterial outer membrane by the chaperone/usher pathway. Cell. 2008; 133(4):640-52. PMC: 3036173. DOI: 10.1016/j.cell.2008.03.033. View

Emtenas H, Alderin L, Almqvist F . An enantioselective ketene-imine cycloaddition method for synthesis of substituted ring-fused 2-pyridinones. J Org Chem. 2001; 66(20):6756-61. DOI: 10.1021/jo015794u. View

Berg V, Sellstedt M, Hedenstrom M, Pinkner J, Hultgren S, Almqvist F . Design, synthesis and evaluation of peptidomimetics based on substituted bicyclic 2-pyridones-targeting virulence of uropathogenic E. coli. Bioorg Med Chem. 2006; 14(22):7563-81. DOI: 10.1016/j.bmc.2006.07.017. View

Waksman G, Hultgren S . Structural biology of the chaperone-usher pathway of pilus biogenesis. Nat Rev Microbiol. 2009; 7(11):765-74. PMC: 3790644. DOI: 10.1038/nrmicro2220. View

Hung D, Knight S, Woods R, Pinkner J, Hultgren S . Molecular basis of two subfamilies of immunoglobulin-like chaperones. EMBO J. 1996; 15(15):3792-805. PMC: 452060. View

10.

Sellstedt M, Almqvist F . Synthesis of a novel tricyclic peptidomimetic scaffold. Org Lett. 2008; 10(18):4005-7. DOI: 10.1021/ol801506y. View

11.

Boucher H, Talbot G, Bradley J, Edwards J, Gilbert D, Rice L . Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2008; 48(1):1-12. DOI: 10.1086/595011. View

12.

Cegelski L, Marshall G, Eldridge G, Hultgren S . The biology and future prospects of antivirulence therapies. Nat Rev Microbiol. 2007; 6(1):17-27. PMC: 2211378. DOI: 10.1038/nrmicro1818. View

13.

Hung D, Hultgren S . Pilus biogenesis via the chaperone/usher pathway: an integration of structure and function. J Struct Biol. 1999; 124(2-3):201-20. DOI: 10.1006/jsbi.1998.4049. View

14.

Verger D, Miller E, Remaut H, Waksman G, Hultgren S . Molecular mechanism of P pilus termination in uropathogenic Escherichia coli. EMBO Rep. 2006; 7(12):1228-32. PMC: 1794691. DOI: 10.1038/sj.embor.7400833. View

15.

Nishiyama M, Horst R, Eidam O, Herrmann T, Ignatov O, Vetsch M . Structural basis of chaperone-subunit complex recognition by the type 1 pilus assembly platform FimD. EMBO J. 2005; 24(12):2075-86. PMC: 1150887. DOI: 10.1038/sj.emboj.7600693. View

16.

Pinkner J, Remaut H, Buelens F, Miller E, Aberg V, Pemberton N . Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria. Proc Natl Acad Sci U S A. 2006; 103(47):17897-902. PMC: 1693844. DOI: 10.1073/pnas.0606795103. View

17.

OToole G, Kolter R . Initiation of biofilm formation in Pseudomonas fluorescens WCS365 proceeds via multiple, convergent signalling pathways: a genetic analysis. Mol Microbiol. 1998; 28(3):449-61. DOI: 10.1046/j.1365-2958.1998.00797.x. View

18.

Chorell E, Das P, Almqvist F . Diverse functionalization of thiazolo ring-fused 2-pyridones. J Org Chem. 2007; 72(13):4917-24. DOI: 10.1021/jo0704053. View

19.

Vetsch M, Puorger C, Spirig T, Grauschopf U, Weber-Ban E, Glockshuber R . Pilus chaperones represent a new type of protein-folding catalyst. Nature. 2004; 431(7006):329-33. DOI: 10.1038/nature02891. View

20.

Aberg V, Almqvist F . Pilicides-small molecules targeting bacterial virulence. Org Biomol Chem. 2007; 5(12):1827-34. DOI: 10.1039/b702397a. View