Design, synthesis and evaluation of peptidomimetics based on substituted bicyclic 2-pyridones—Targeting virulence of uropathogenic E. coli

Åberg, Veronica; Sellstedt, Magnus; Hedenström, Mattias; Pinkner, Jerome S.; Hultgren, Scott J.; Almqvist, Fredrik

doi:10.1016/j.bmc.2006.07.017

Cited by 54 publications

(47 citation statements)

References 46 publications

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“…[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. [26] Interestingly, the crystal structure of the complex of 14 with the chaperone PapD contradicted the initial hypothesis of 13 as a mimic of PapG binding in the cleft of PapD: 14 is bound to a remote lipophilic patch on PapD.…”

Section: Ta Rgeting Quorum Sensingmentioning

confidence: 99%

“…Promising results, especially from interference with quorum sensing and adhesins, must now be further translated into early clinical phases to prevent the aforementioned scenarios of untreatable infections with Gram-negative bacteria. (17)(18)(19) and PapG (20,21), and P. aeruginosa LecA (23)(24)(25) and LecB (26)(27)(28)(29).…”

Section: Ta Rgeting Quorum Sensingmentioning

confidence: 99%

“…Inappropriate and excessive use, both as therapeutic for humans and as preventive food additive in meat production, has imposed a high selection pressure on bacteria and resistant mutants appeared. Antibiotic-resistant strains now pose a major problem in health care units and nosocomial infections by resistant strains led to 25'000 deaths and extra costs of € 900 million in the European Union in 2007. [1] Methicillin-resistant Staphylococcus aureus (MRSA) is a prominent Gram-positive bacterium and in recent years, resistant strains of Gram-negative Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa appeared in hospital-acquired infections.…”

Section: Introductionmentioning

confidence: 99%

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

Sommer

Joachim²,

Wagner³

et al. 2013

Chimia

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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.

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Section: Ta Rgeting Quorum Sensingmentioning

confidence: 99%

Section: Ta Rgeting Quorum Sensingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Sommer

Joachim²,

Wagner³

et al. 2013

Chimia

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Section: 16e)mentioning

confidence: 99%

“…A new synthetic method allowed the exploitation of position R3 for refining solubility (Pemberton et al, 2004) and bioavailability. Extensive work on position R3 to extend toward diand tri-peptide mimetics resulted in an increased affinity towards PapD but a reduction in inhibition of pili formation (Berg et al, 2006, Aberg & Almqvist, 2007.Interestingly, NMR studies of peptidomimetics such as 6C and 6E showed three different binding locations on FlimC , all leading to a defect in pili formation by preventing correct folding of the chaperone or by interfering directly with the protein-protein interaction with FimH. These compounds successfully inhibited pili and curli (another bacterial fiber (Barnhart & Chapman, 2006)) formation (Cegelski et al, 2009, Chorell et al, 2012.…”

mentioning

confidence: 99%

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

Duprez¹

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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...

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Synthesis and Characterization of a Multi Ring‐Fused 2‐Pyridone‐Based Fluorescent Scaffold

et al. 2010

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Design, synthesis and evaluation of peptidomimetics based on substituted bicyclic 2-pyridones—Targeting virulence of uropathogenic E. coli

Cited by 54 publications

References 46 publications

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

Synthesis and Characterization of a Multi Ring‐Fused 2‐Pyridone‐Based Fluorescent Scaffold

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