Design, synthesis and biological evaluation of mannosyl triazoles as FimH antagonists

Schwardt, Oliver; Rabbani, Said; Hartmann, Margrit; Abgottspon, Daniela; Wittwer, Matthias; Kleeb, Simon; Zalewski, Adam; Smieško, Martin; Cutting, Brian; Ernst, Beat

doi:10.1016/j.bmc.2011.08.057

Cited by 80 publications

(77 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6 D and E) (82-85). High-affinity mannosides that bind in the FimH binding pocket have been shown to block invasion and IBC formation as well as biofilm formation on abiotic surfaces (82,83). Additionally, mannosides delivered orally were shown to dramatically reduce bacterial burden during chronic cystitis (Fig.…”

Section: Discussionmentioning

confidence: 99%

Positively selected FimH residues enhance virulence during urinary tract infection by altering FimH conformation

Schwartz¹,

Kalas²,

Pinkner³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

118

102

View full text Add to dashboard Cite

Significance The evolution of multidrug resistance in pathogenic bacteria, including uropathogenic Escherichia coli (UPEC), that cause most urinary tract infections is becoming a worldwide crisis. UPEC use a variety of virulence factors and adhesins, including the mannose-binding FimH adhesin, to colonize and invade bladder tissue, often forming intracellular biofilms and quiescent reservoirs that can contribute to recurrent infections recalcitrant to treatment. Using two prototypical UPEC strains, we discovered that positively selected residues outside of the FimH mannose-binding pocket affect transitions between low- and high-affinity FimH conformations, which extraordinarily impacts FimH function during pathogenesis. Thus, this work elucidates mechanistic and functional insights into pathoadaptation and evolutionary fine-tuning of critical virulence interactions.

show abstract

Section: Discussionmentioning

confidence: 99%

Positively selected FimH residues enhance virulence during urinary tract infection by altering FimH conformation

Schwartz¹,

Kalas²,

Pinkner³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

118

102

View full text Add to dashboard Cite

show abstract

“…[11a, 13] These were followed by derivatives of squaric acid, [14] biphenyls and other diaryls, [15] triazoles, [16] and indolines, [17] among others. We routinelyt est new candidates for in vitro binding to FimH-CRD [15b, [16][17][18] and to UPEC, [19] as well as for efficacy in aU TI mousem odel. [20] As pecial focus is placed on the PK/PD (pharmacokinetic/pharmacodynamic) properties for oral bioavailability.…”

Section: Introductionmentioning

confidence: 99%

The Tyrosine Gate of the Bacterial Lectin FimH: A Conformational Analysis by NMR Spectroscopy and X‐ray Crystallography

et al. 2015

Self Cite

View full text Add to dashboard Cite

Urinary tract infections caused by uropathogenic E. coli are among the most prevalent infectious diseases. The mannose-specific lectin FimH mediates the adhesion of the bacteria to the urothelium, thus enabling host cell invasion and recurrent infections. An attractive alternative to antibiotic treatment is the development of FimH antagonists that mimic the physiological ligand. A large variety of candidate drugs have been developed and characterized by means of in vitro studies and animal models. Here we present the X-ray co-crystal structures of FimH with members of four antagonist classes. In three of these cases no structural data had previously been available. We used NMR spectroscopy to characterize FimH-antagonist interactions further by chemical shift perturbation. The analysis allowed a clear determination of the conformation of the tyrosine gate motif that is crucial for the interaction with aglycone moieties and was not obvious from X-ray structural data alone. Finally, ITC experiments provided insight into the thermodynamics of antagonist binding. In conjunction with the structural information from X-ray and NMR experiments the results provide a mechanism for the often-observed enthalpy-entropy compensation of FimH antagonists that plays a role in fine-tuning of the interaction.

show abstract

“…In addition, with the increasing prevalence of antibiotic resistance among UPEC and other pathogenic bacteria, there is an urgent need for the devel-opment of new and alternative therapeutics (34). Pili assembled by the CU pathway represent a promising target for clinical intervention, and a number of approaches have been taken to develop antipilus therapeutics, including vaccines against pilus proteins, competitive inhibitors of pilus-mediated adhesion, and small molecules that disrupt pilus biogenesis (35)(36)(37)(38)(39)(40)(41)(42). An example of the latter is a class of small molecules termed pilicides, which interfere with the CU pathway and block assembly of P and type 1 pili by UPEC (39,40).…”

mentioning

confidence: 99%

Nitazoxanide Inhibits Pilus Biogenesis by Interfering with Folding of the Usher Protein in the Outer Membrane

Chahales

Hoffman

Thanassi

2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

bMany bacterial pathogens assemble surface fibers termed pili or fimbriae that facilitate attachment to host cells and colonization of host tissues. The chaperone/usher (CU) pathway is a conserved secretion system that is responsible for the assembly of virulence-associated pili by many different Gram-negative bacteria. Pilus biogenesis by the CU pathway requires a dedicated periplasmic chaperone and an integral outer membrane (OM) assembly and secretion platform termed the usher. Nitazoxanide (NTZ), an antiparasitic drug, was previously shown to inhibit the function of aggregative adherence fimbriae and type 1 pili assembled by the CU pathway in enteroaggregative Escherichia coli, an important causative agent of diarrhea. We show here that NTZ also inhibits the function of type 1 and P pili from uropathogenic E. coli (UPEC). UPEC is the primary causative agent of urinary tract infections, and type 1 and P pili mediate colonization of the bladder and kidneys, respectively. By analysis of the different stages of the CU pilus biogenesis pathway, we show that treatment of bacteria with NTZ causes a reduction in the number of usher molecules in the OM, resulting in a loss of pilus assembly on the bacterial surface. In addition, we determine that NTZ specifically prevents proper folding of the usher ␤-barrel domain in the OM. Our findings demonstrate that NTZ is a pilicide with a novel mechanism of action and activity against diverse CU pathways. This suggests that further development of the NTZ scaffold may lead to new antivirulence agents that target the usher to prevent pilus assembly.

show abstract

Design, synthesis and biological evaluation of mannosyl triazoles as FimH antagonists

Cited by 80 publications

References 71 publications

Positively selected FimH residues enhance virulence during urinary tract infection by altering FimH conformation

Positively selected FimH residues enhance virulence during urinary tract infection by altering FimH conformation

The Tyrosine Gate of the Bacterial Lectin FimH: A Conformational Analysis by NMR Spectroscopy and X‐ray Crystallography

Nitazoxanide Inhibits Pilus Biogenesis by Interfering with Folding of the Usher Protein in the Outer Membrane

Contact Info

Product

Resources

About