Design and Evaluation of Pilicides: Potential Novel Antibacterial Agents Directed Against UropathogenicEscherichia coli

Svensson, Åsa; Larsson, Andreas; Emtenäs, Hans; Hedenström, Mattias; Fex, Tomas; Hultgren, Scott J.; Pinkner, Jerome S.; Almqvist, Fredrik; Kihlberg, Jan

doi:10.1002/1439-7633(20011203)2:12<915::aid-cbic915>3.0.co;2-m

Cited by 116 publications

(64 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The atomiclevel structural details of chaperone-subunit interactions and the potential to inhibit pilus biogenesis stimulated the rational design and synthesis of small molecular inhibitors of pilus assembly, termed pilicides. The R8͞K112 cleft region of the chaperone was originally targeted (20,21), followed by compounds 1a and 1b with two substituents (R 1 and R 2 , Fig. 1) (22)(23)(24) that bound to PapD and FimC, the P and type 1 pili chaperones, respectively (21,22,25).…”

mentioning

confidence: 99%

Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria

Pinkner

Remaut

Buelens

et al. 2006

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

Self Cite

263

245

View full text Add to dashboard Cite

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

show abstract

mentioning

confidence: 99%

Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria

Pinkner

Remaut

Buelens

et al. 2006

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

Self Cite

263

245

View full text Add to dashboard Cite

show abstract

“…3) were designed mimetics of the pilus subunit PapG in its interaction with the chaperone PapD with micromolar potencies. [24] To improve the poor solubility of these lipophilic compounds, amines were introduced into pilicide 13, resulting in reduced affinity for the chaperone and potency in live bacteria, which was tentatively assigned to a weakened permeability of the more hydrophilic compound across the bacterial membrane. [25] Later, the morpholino derivative 14 was able to disrupt pilus biogenesis of the uropathogenic E. coli strain UTI89 (IC 50 = 180-360 µM) and thereby disrupt adherence to host cells and biofilm formation.…”

Section: Ta Rgeting Quorum Sensingmentioning

confidence: 99%

New Approaches to Control Infections: Anti-biofilm Strategies against Gram-negative Bacteria

Sommer

Joachim²,

Wagner³

et al. 2013

Chimia

View full text Add to dashboard Cite

Hospital-acquired bacterial infections, especially with Gram-negative pathogens, present a major threat due to the rapid spread of antibiotic-resistant strains. Targeting mechanisms of bacterial virulence has recently appeared as a promising new therapeutic paradigm. Biofilm formation is a bacterial lifestyle, which offers a survival advantage through its protective matrix against host immune defense and antibiotic treatment. Interfering with biogenesis of adhesive organelles, bacterial communication or carbohydrate-mediated adhesion as anti-biofilm strategies are reviewed.

show abstract

“…inhibited PapG-PapD complex formation (Karlsson et al, 1998). A 3.0 Å resolution PapD-PapG 307-314 complex crystal structure allowed the development of two peptidomimetic scaffolds using computational docking and surface plasmon resonance (Svensson et al, 2001). The first scaffold retained a peptide backbone and had non-natural side chains (Figure 1.16B), whereas the second incorporated a 2-pyridinone scaffold (Figure 1.16C, Amino methylated 2-pyridinone -Patent # US7915417).…”

Section: I38 De Novo Scaffold: Design Of Pilicides and Curlicidesmentioning

confidence: 99%

“…The first scaffold retained a peptide backbone and had non-natural side chains (Figure 1.16B), whereas the second incorporated a 2-pyridinone scaffold (Figure 1.16C, Amino methylated 2-pyridinone -Patent # US7915417). , Svensson et al, 2001, Karlsson et al, 1998, Pemberton et al, 2004). …”

Section: I38 De Novo Scaffold: Design Of Pilicides and Curlicidesmentioning

confidence: 99%

See 1 more Smart Citation

Design, synthesis and evaluation of peptides and peptidomimetics inhibiting the bacterial DsbA-DsbB interaction

Duprez¹

View full text Add to dashboard Cite

The rapid development and dissemination of antibiotic resistance in pathogenic bacteria requires new strategies and new structural scaffolds of antimicrobial compounds to be investigated. A developing trend targets virulence factors rather than pathways essential for survival in an effort to neutralize pathogens while minimizing the risk of resistance. The thesis focuses on the design of new molecules from peptides to peptidomimetics aimed at disrupting the bacterial periplasmic oxidative system, a new antivirulence target.This thesis initially describes in chapter I the recent emergence of peptidomimetics in antimicrobial treatments aimed at well-known mechanisms as well as novel targets.Peptidomimetics may be particularly efficient for disrupting protein-protein interactions and have been successful for instance in preventing post-translational modifications or the formation of pili machinery. The thesis also highlights the mechanism and context of the interaction between DsbA and DsbB, both primary factors in the periplasmic oxidative system of gram-negative bacteria and the target proteins of this PhD.Developing inhibitors requires a solid screening pipeline of biophysical assays to measure binding parameters such as affinity, thermodynamics and kinetics. Chapter II highlights the building and optimization of such a pipeline by evaluating differential scanning fluorimetry, isothermal titration calorimetry, surface plasmon resonance, substrate oxidation assay and crystallography in order to characterize the designed peptide scaffolds.Chapter III focuses on the structure-activity relationship studies of 31 manually synthesized peptide sequences screened through this pipeline. Based on peptide length scouting, alanine scanning and rational substitution of specific residues, a final heptameric peptide was found to bind Escherichia coli DsbA with a Kd of 2.9 ± 0.3 µM. Moreover, the data suggest a probable disulfide bond formation between peptide and DsbA essential to the binding interface, while cysteine-free peptides present very weak affinity towards EcDsbA. This chapter generated a manuscript submitted to the Journal of Medicinal Chemistry.iiiIn a slightly different strategy, Chapter IV evaluates this best heptamer peptide sequence against a newly characterized Proteus Mirabilis DsbA, a structurally related protein (59% similarity with E. coli DsbA) showing promise for co-crystallization. With the peptide showing the same affinity against wild type E. coli and P. mirabilis DsbA, a highresolution (1.6 Å) co-crystal structure of the heptamer peptide bound to a cysteine mutant of P. mirabilis DsbA was solved. This structure shows the peptide binding to the P.mirabilis DsbA active site in a similar fashion to the native E. coli DsbA/DsbB interaction and differently from E. coli DsbA substrates. In-depth analysis of the high-resolution structure identifies two binding anchors, a H-bond-rich region and a hydrophobic pocket, which can be optimized for tighter affinities. This chapter generated a manuscript su...

show abstract

Design and Evaluation of Pilicides: Potential Novel Antibacterial Agents Directed Against UropathogenicEscherichia coli

Cited by 116 publications

References 18 publications

Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria

Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria

New Approaches to Control Infections: Anti-biofilm Strategies against Gram-negative Bacteria

Design, synthesis and evaluation of peptides and peptidomimetics inhibiting the bacterial DsbA-DsbB interaction

Contact Info

Product

Resources

About