Rameshwar U. Kadam
University of Bern
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Featured researches published by Rameshwar U. Kadam.
Chemistry & Biology | 2008
Emma M. V. Johansson; Shanika A. Crusz; Elena Kolomiets; Lieven Buts; Rameshwar U. Kadam; Martina Cacciarini; Kai-Malte Bartels; Stephen P. Diggle; Miguel Cámara; Paul Williams; Remy Loris; Cristina Nativi; Frank Rosenau; Karl-Erich Jaeger; Tamis Darbre; Jean-Louis Reymond
The human pathogenic bacterium Pseudomonas aeruginosa produces a fucose-specific lectin, LecB, implicated in tissue attachment and the formation of biofilms. To investigate if LecB inhibition disrupts these processes, high-affinity ligands were obtained by screening two 15,536-member combinatorial libraries of multivalent fucosyl-peptide dendrimers. The most potent LecB-ligands identified were dendrimers FD2 (C-Fuc-LysProLeu)(4)(LysPheLysIle)(2)LysHisIleNH(2) (IC(50) = 0.14 microM by ELLA) and PA8 (OFuc-LysAlaAsp)(4)(LysSerGlyAla)(2)LysHisIleNH(2) (IC(50) = 0.11 microM by ELLA). Dendrimer FD2 led to complete inhibition of P. aeruginosa biofilm formation (IC(50) approximately 10 microM) and induced complete dispersion of established biofilms in the wild-type strain and in several clinical P. aeruginosa isolates. These experiments suggest that LecB inhibition by high-affinity multivalent ligands could represent a therapeutic approach against P. aeruginosa infections by inhibition of biofilm formation and dispersion of established biofilms.
Angewandte Chemie | 2011
Rameshwar U. Kadam; Myriam Bergmann; Matthew Hurley; Divita Garg; Martina Cacciarini; Magdalena A. Swiderska; Cristina Nativi; Michael Sattler; Alan Smyth; Paul Williams; Miguel Cámara; Achim Stocker; Tamis Darbre; Jean-Louis Reymond
Biofilm inhibition is achieved with a phenylgalactosyl peptide dendrimer (see picture) that binds to the galactose-specific lectin LecA of P. aeruginosa. The multivalency of the ligands is critical for biofilm inhibition, although the nature of the linker between the peptide dendrimer and the galactose can provide additional contacts to the lectin and also has an effect on the interaction.
ChemMedChem | 2009
Elena Kolomiets; Magdalena A. Swiderska; Rameshwar U. Kadam; Emma M. V. Johansson; Karl-Erich Jaeger; Tamis Darbre; Jean-Louis Reymond
Dendritic antibacterial agents: Glycopeptide dendrimer biofilm inhibitors were synthesized combinatorially and optimized for binding to the fucose‐specific lectin LecB, which has high affinity of fucose. These dendritic ligands are potential antibacterial agents against Pseudomonas aeruginosa, an antibiotic resistant human pathogen.
ACS Chemical Biology | 2013
Rameshwar U. Kadam; Divita Garg; Julian Schwartz; Ricardo Visini; Michael Sattler; Achim Stocker; Tamis Darbre; Jean-Louis Reymond
The galactose specific lectin LecA mediates biofilm formation in the opportunistic pathogen P. aeruginosa . The interaction between LecA and aromatic β-galactoside biofilm inhibitors involves an intermolecular CH-π T-shape interaction between C(ε1)-H of residue His50 in LecA and the aromatic ring of the galactoside aglycone. The generality of this interaction was tested in a diverse family of β-galactosides. LecA binding to aromatic β-galactosides (KD ∼ 8 μM) was consistently stronger than to aliphatic β-galactosides (KD ∼ 36 μM). The CH-π interaction was observed in the X-ray crystal structures of six different LecA complexes, with shorter than the van der Waals distances indicating productive binding. Related XH/cation/π-π interactions involving other residues were identified in complexes of aromatic glycosides with a variety of carbohydrate binding proteins such as concanavalin A. Exploiting such interactions might be generally useful in drug design against these targets.
MedChemComm | 2012
Michaela Stach; Noélie Maillard; Rameshwar U. Kadam; David Kalbermatter; Marcel Meury; Malcolm G. P. Page; Dimitrios Fotiadis; Tamis Darbre; Jean-Louis Reymond
Antimicrobial peptide dendrimer H1 Leu8(Lys-Leu)4(Lys-Phe)2Lys-LysNH2 (Lys = branching lysine) was identified by screening a 6750-membered combinatorial library by the bead-diffusion assay. Sequence variations also revealed dendrimer bH1 Leu8(Dap-Leu)4(Dap-Phe)2Dap-LysNH2 (Dap = branching 2,3-diaminopropanoic acid) as a more potent analog. H1 and bH1 showed good antimicrobial activities mediated by membrane disruption (MIC = 2–4 μg mL−1 on Bacillus subtilis and Escherichia coli) but low hemolytic activity (MHC = 310 μg mL−1 respectively >2000 μg mL−1).
Chemistry: A European Journal | 2013
Rameshwar U. Kadam; Myriam Bergmann; Divita Garg; Gabriele Gabrieli; Achim Stocker; Tamis Darbre; Jean-Louis Reymond
The galactopeptide dendrimer GalAG2 ((β-Gal-OC6H4CO-Lys-Pro-Leu)4(Lys-Phe-Lys-Ile)2Lys-His-Ile-NH2) binds strongly to the Pseudomonas aeruginosa (PA) lectin LecA, and it inhibits PA biofilms, as well as disperses already established ones. By starting with the crystal structure of the terminal tripeptide moiety GalA-KPL in complex with LecA, a computational mutagenesis study was carried out on the galactotripeptide to optimize the peptide-lectin interactions. 25 mutants were experimentally evaluated by a hemagglutination inhibition assay, 17 by isothermal titration calorimetry, and 3 by X-ray crystallography. Two of these tripeptides, GalA-KPY (dissociation constant (K(D))=2.7 μM) and GalA-KRL (K(D)=2.7 μM), are among the most potent monovalent LecA ligands reported to date. Dendrimers based on these tripeptide ligands showed improved PA biofilm inhibition and dispersal compared to those of GalAG2, particularly G2KPY ((β-Gal-OC6H4CO-Lys-Pro-Tyr)4(Lys-Phe-Lys-Ile)2Lys-His-Ile-NH2). The possibility to retain and even improve the biofilm inhibition in several analogues of GalAG2 suggests that it should be possible to fine-tune this dendrimer towards therapeutic use by adjusting the pharmacokinetic parameters in addition to the biofilm inhibition through amino acid substitutions.
ChemBioChem | 2010
Nicolas A. Uhlich; Antonino Natalello; Rameshwar U. Kadam; Silvia Maria Doglia; Jean-Louis Reymond; Tamis Darbre
The third‐generation peptide‐dendrimer B1 (AcES)8(BEA)4(K‐Amb‐Y)2BCD‐NH2 (B=branching (S)‐2,3‐diaminopropanoic acid, K=branching lysine, Amb=4‐aminomethyl‐benzoic acid) is the first synthetic model for cobalamin‐binding proteins and binds cobalamin strongly (Ka=5.0×106 M−1) and rapidly (k2=346 M−1 s−1) by coordination of cobalt to the cysteine residue at the dendrimer core. A structure–activity relationship study is reported concerning the role of negative charges in binding. Substituting glutamates (E) for glutamines (Q) in the outer branches of B1 to form N3 (AcQS)8(BQA)4(B‐Amb‐Y)2BCD‐NH2 leads to stronger (Ka=12.0×106 M−1) but slower (k2=67 M−1 s−1) cobalamin binding. CD and FTIR spectra show that the dendrimers and their cobalamin complexes exist as random‐coil structures without aggregation in solution. The hydrodynamic radii of the dendrimers determined by diffusion NMR either remains constant or slightly decreases upon binding to cobalamin; this indicates the formation of compact, presumably hydrophobically collapsed complexes.
Chemical Biology & Drug Design | 2008
Rameshwar U. Kadam; Joana Tavares; V.M. Kiran; Anabela Cordeiro; Ali Ouaissi; Nilanjan Roy
Novel anti‐leishmanial target LmSir2 has few subtle but prudent structural differences in ligand binding and catalytic domain as compared to its human counterpart. In silico screening and validation followed by in vitro deacetylation and cell killing assays described herein give a proof of concept for development of strategies exploiting such minor differences for screening libraries of small molecules to identify selective inhibitors.
Chemical Communications | 2011
Marco Bartoloni; Rameshwar U. Kadam; Julian Schwartz; Julien Furrer; Tamis Darbre; Jean-Louis Reymond
Norbornapeptides (bicyclo[2.2.1]heptapeptides) and related bicyclic homodetic peptides were prepared by solid-phase peptide synthesis using an orthogonal protection scheme. These conformationally rigid peptides cover an almost pristine area of peptide topological space and adopt globular shapes similar to those of short α-helical peptides.
Chemical Biology & Drug Design | 2007
Rameshwar U. Kadam; Divita Garg; Nilanjan Roy
UDP‐3‐O‐[R‐3‐hydroxymyristoyl]‐GlcNAc deacetylase enzyme of Pseudomonas aeruginosa is an interesting target for development of anti‐infective drugs against this gram‐negative bacterium. Many segregated studies analyzing the P. aeruginosa UDP‐3‐O‐[R‐3‐hydroxymyristoyl]‐GlcNAc deacetylase and its inhibitors have been reported in the recent past. In the present study, an attempt has been made to integrate this knowledge for the development of an effective multilayer screening approach. Eventually, an extensive chemical space was screened to filter out three potential P. aeruginosa UDP‐3‐O‐[R‐3‐hydroxymyristoyl]‐GlcNAc deacetylase inhibitors.