Antivirulence Isoquinolone Mannosides: Optimization of the Biaryl Aglycone for FimH Lectin Binding Affinity and Efficacy in the Treatment of Chronic UTI.

Uropathogenic E. coli (UPEC) employ the mannose-binding adhesin FimH to colonize the bladder epithelium during urinary tract infection (UTI). Previously reported FimH antagonists exhibit good potency and efficacy, but low bioavailability and a short half-life in vivo.

Combinatorial small-molecule therapy prevents uropathogenic Escherichia coli catheter-associated urinary tract infections in mice.

Catheter-associated urinary tract infections (CAUTIs) constitute the majority of nosocomial urinary tract infections (UTIs) and pose significant clinical challenges. These infections are polymicrobial in nature and are often associated with multidrug-resistant pathogens, including uropathogenic Escherichia coli (UPEC). Urinary catheterization elicits major histological and immunological alterations in the bladder that can favor microbial colonization and dissemination in the urinary tract.

Distinguishing the contribution of type 1 pili from that of other QseB-misregulated factors when QseC is absent during urinary tract infection.

Urinary tract infections (UTI), primarily caused by uropathogenic Escherichia coli (UPEC), are one of the leading bacterial infections due to their high frequency and rate of recurrence. Both type 1 pilus adhesive organelles (fim) and the QseC sensor kinase have been implicated in UPEC virulence during UTI and have been individually reported to be promising drug targets. Deletion of qseC leads to pleiotropic effects due to unregulated activation of the cognate response regulator QseB, influencing conserved metabolic processes and diminishing expression of virulence genes, including type 1 pili.

Lead optimization studies on FimH antagonists: discovery of potent and orally bioavailable ortho-substituted biphenyl mannosides.

Herein, we describe the X-ray structure-based design and optimization of biaryl mannoside FimH inhibitors. Diverse modifications to the biaryl ring to improve druglike physical and pharmacokinetic properties of mannosides were assessed for FimH binding affinity based on their effects on hemagglutination and biofilm formation along with direct FimH binding assays. Substitution on the mannoside phenyl ring ortho to the glycosidic bond results in large potency enhancements several-fold higher than those of corresponding unsubstituted matched pairs and can be rationalized from increased hydrophobic interactions with the FimH hydrophobic ridge (Ile13) or "tyrosine gate" (Tyr137 and Tyr48) also lined by Ile52.

Design and synthesis of fluorescent pilicides and curlicides: bioactive tools to study bacterial virulence mechanisms.

Pilicides and curlicides are compounds that block the formation of the virulence factors pili and curli, respectively. To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized. This was achieved by using a strategy based on structure-activity knowledge, in which key pilicide and curlicide substituents on the ring-fused dihydrothiazolo 2-pyridone central fragment were replaced by fluorophores.

Treatment and prevention of urinary tract infection with orally active FimH inhibitors.

Chronic and recurrent urinary tract infections pose a serious medical problem because there are few effective treatment options. Patients with chronic urinary tract infections are commonly treated with long-term prophylactic antibiotics that promote the development of antibiotic-resistant forms of uropathogenic Escherichia coli (UPEC), further complicating treatment. We developed small-molecular weight compounds termed mannosides that specifically inhibit the FimH type 1 pilus lectin of UPEC, which mediates bacterial colonization, invasion, and formation of recalcitrant intracellular bacterial communities in the bladder epithelium.

Structure-based drug design and optimization of mannoside bacterial FimH antagonists.

FimH-mediated cellular adhesion to mannosylated proteins is critical in the ability of uropathogenic E. coli (UPEC) to colonize and invade the bladder epithelium during urinary tract infection. We describe the discovery and optimization of potent small-molecule FimH bacterial adhesion antagonists based on alpha-d-mannose 1-position anomeric glycosides using X-ray structure-guided drug design.

Virulence plasmid harbored by uropathogenic Escherichia coli functions in acute stages of pathogenesis.

Urinary tract infections (UTIs), the majority of which are caused by uropathogenic Escherichia coli (UPEC), afflict nearly 60% of women within their lifetimes. Studies in mice and humans have revealed that UPEC strains undergo a complex pathogenesis cycle that involves both the formation of intracellular bacterial communities (IBC) and the colonization of extracellular niches. Despite the commonality of the UPEC pathogenesis cycle, no specific urovirulence genetic profile has been determined; this is likely due to the fluid nature of the UPEC genome as the result of horizontal gene transfer and numerous genes of unknown function.

Positive selection identifies an in vivo role for FimH during urinary tract infection in addition to mannose binding.

FimH, the type 1 pilus adhesin of uropathogenic Escherichia coli (UPEC), contains a receptor-binding domain with an acidic binding pocket specific for mannose. The fim operon, and thus type 1 pilus production, is under transcriptional control via phase variation of an invertible promoter element. FimH is critical during urinary tract infection for mediating colonization and invasion of the bladder epithelium and establishment of intracellular bacterial communities (IBCs).

Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation.

Curli are functional extracellular amyloid fibers produced by uropathogenic Escherichia coli (UPEC) and other Enterobacteriaceae. Ring-fused 2-pyridones, such as FN075 and BibC6, inhibited curli biogenesis in UPEC and prevented the in vitro polymerization of the major curli subunit protein CsgA. The curlicides FN075 and BibC6 share a common chemical lineage with other ring-fused 2-pyridones termed pilicides.

Bacterial adhesion--a source of alternate antibiotic targets.

The prevalence of antibiotic resistance among microorganisms that cause infectious diseases has resulted in the need to devise new strategies for the development of novel therapeutics. In an effort to thwart antibiotic resistance, novel therapeutics are being developed that target bacterial virulence factors as an alternative to traditional antibiotics, which target essential microbial processes, thereby promoting bacterial evolution and resulting in resistance. While many antivirulence targets exist, this feature review focuses on adhesion as an antivirulence target, using pili of uropathogenic Escherichia coli as a model system.