ChemMedChemVolume 2, Issue 10 p. 1414-1417 Communication Naphthyl Tetronic Acids as Multi-Target Inhibitors of Bacterial Peptidoglycan Biosynthesis Tarek S. Mansour Dr., Tarek S. Mansour Dr. mansout@wyeth.com Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA, Fax: (+1) 845-602-5580Search for more papers by this authorCraig E. Caufield Dr., Craig E. Caufield Dr. Wyeth Research, CN 8000, Princeton, NJ 08543, USASearch for more papers by this authorBeth Rasmussen Dr., Beth Rasmussen Dr. Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA, Fax: (+1) 845-602-5580Search for more papers by this authorRajiv Chopra Dr., Rajiv Chopra Dr. Wyeth Research, Cambridge, MA 02140, USASearch for more papers by this authorGirija Krishnamurthy Dr., Girija Krishnamurthy Dr. Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA, Fax: (+1) 845-602-5580Search for more papers by this authorKoi M. Morris, Koi M. Morris Wyeth Research, CN 8000, Princeton, NJ 08543, USASearch for more papers by this authorKristine Svenson, Kristine Svenson Wyeth Research, Cambridge, MA 02140, USASearch for more papers by this authorJoel Bard Dr., Joel Bard Dr. Wyeth Research, Cambridge, MA 02140, USASearch for more papers by this authorClaudia Smeltzer, Claudia Smeltzer Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA, Fax: (+1) 845-602-5580Search for more papers by this authorShaughnessy Naughton, Shaughnessy Naughton Wyeth Research, CN 8000, Princeton, NJ 08543, USASearch for more papers by this authorSchuyler Antane, Schuyler Antane Wyeth Research, CN 8000, Princeton, NJ 08543, USASearch for more papers by this authorYoujun Yang Dr., Youjun Yang Dr. Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA, Fax: (+1) 845-602-5580Search for more papers by this authorAnatoly Severin Dr., Anatoly Severin Dr. Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA, Fax: (+1) 845-602-5580Search for more papers by this authorDominick Quagliato Dr., Dominick Quagliato Dr. Wyeth Research, CN 8000, Princeton, NJ 08543, USASearch for more papers by this authorPeter J. Petersen, Peter J. Petersen Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA, Fax: (+1) 845-602-5580Search for more papers by this authorGuy Singh Dr., Guy Singh Dr. Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA, Fax: (+1) 845-602-5580Search for more papers by this author Tarek S. Mansour Dr., Tarek S. Mansour Dr. mansout@wyeth.com Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA, Fax: (+1) 845-602-5580Search for more papers by this authorCraig E. Caufield Dr., Craig E. Caufield Dr. Wyeth Research, CN 8000, Princeton, NJ 08543, USASearch for more papers by this authorBeth Rasmussen Dr., Beth Rasmussen Dr. Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA, Fax: (+1) 845-602-5580Search for more papers by this authorRajiv Chopra Dr., Rajiv Chopra Dr. Wyeth Research, Cambridge, MA 02140, USASearch for more papers by this authorGirija Krishnamurthy Dr., Girija Krishnamurthy Dr. Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA, Fax: (+1) 845-602-5580Search for more papers by this authorKoi M. Morris, Koi M. Morris Wyeth Research, CN 8000, Princeton, NJ 08543, USASearch for more papers by this authorKristine Svenson, Kristine Svenson Wyeth Research, Cambridge, MA 02140, USASearch for more papers by this authorJoel Bard Dr., Joel Bard Dr. Wyeth Research, Cambridge, MA 02140, USASearch for more papers by this authorClaudia Smeltzer, Claudia Smeltzer Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA, Fax: (+1) 845-602-5580Search for more papers by this authorShaughnessy Naughton, Shaughnessy Naughton Wyeth Research, CN 8000, Princeton, NJ 08543, USASearch for more papers by this authorSchuyler Antane, Schuyler Antane Wyeth Research, CN 8000, Princeton, NJ 08543, USASearch for more papers by this authorYoujun Yang Dr., Youjun Yang Dr. Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA, Fax: (+1) 845-602-5580Search for more papers by this authorAnatoly Severin Dr., Anatoly Severin Dr. Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA, Fax: (+1) 845-602-5580Search for more papers by this authorDominick Quagliato Dr., Dominick Quagliato Dr. Wyeth Research, CN 8000, Princeton, NJ 08543, USASearch for more papers by this authorPeter J. Petersen, Peter J. Petersen Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA, Fax: (+1) 845-602-5580Search for more papers by this authorGuy Singh Dr., Guy Singh Dr. Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA, Fax: (+1) 845-602-5580Search for more papers by this author First published: 26 September 2007 https://doi.org/10.1002/cmdc.200700094Citations: 37Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract A pathway screen targeting multiple muramyl peptide synthesis inhibitors identified the naphthyl tetronic acids series. Optimization of this series based on IC50, Kd and MIC values led to potent inhibitors. Compound 5 h was co-crystallized in the active site of E. coli Mur B. Citing Literature Volume2, Issue10October 8, 2007Pages 1414-1417 RelatedInformation

ABSTRACT A series of 3,5-dioxopyrazolidines was identified as novel inhibitors of UDP- N -acetylenolpyruvylglucosamine reductase (MurB). Compounds 1 to 3, which are 1,2-bis(4-chlorophenyl)-3,5-dioxopyrazolidine-4-carboxamides, inhibited Escherichia coli MurB, Staphyloccocus aureus MurB, and E. coli MurA with 50% inhibitory concentrations (IC 50 s) in the range of 4.1 to 6.8 μM, 4.3 to 10.3 μM, and 6.8 to 29.4 μM, respectively. Compound 4, a C-4-unsubstituted 1,2-bis(3,4-dichlorophenyl)-3,5-dioxopyrazolidine, showed moderate inhibitory activity against E. coli MurB, S. aureus MurB, and E. coli MurC (IC 50 s, 24.5 to 35 μM). A fluorescence-binding assay indicated tight binding of compound 3 with E. coli MurB, giving a dissociation constant of 260 nM. Structural characterization of E. coli MurB was undertaken, and the crystal structure of a complex with compound 4 was obtained at 2.4 Å resolution. The crystal structure indicated the binding of a compound at the active site of MurB and specific interactions with active-site residues and the bound flavin adenine dinucleotide cofactor. Peptidoglycan biosynthesis studies using a strain of Staphylococcus epidermidis revealed reduced peptidoglycan biosynthesis upon incubation with 3,5-dioxopyrazolidines, with IC 50 s of 0.39 to 11.1 μM. Antibacterial activity was observed for compounds 1 to 3 (MICs, 0.25 to 16 μg/ml) and 4 (MICs, 4 to 8 μg/ml) against gram-positive bacteria including methicillin-resistant S. aureus , vancomycin-resistant Enterococcus faecalis , and penicillin-resistant Streptococcus pneumoniae .

10.1128/AAC.50.2.556-564.2006. 2006, 50(2):556. DOI: Antimicrob. Agents Chemother. Tarek S. Mansour S. Shumsky, Kristina M. K. Kutterer, Adam Gilbert and David M. Shlaes, Beth A. Rasmussen, Amedeo A. Failli, Jay Kristine Svenson, Peter J. Petersen, Pornpen Labthavikul, Krishnamurthy, Guy Singh, William Hu, David Keeney, Youjun Yang, Anatoly Severin, Rajiv Chopra, Girija Gram-Positive Bacteria Reductase (MurB) with Activity against Acetylenolpyruvylglucosamine N UDP3,5-Dioxopyrazolidines, Novel Inhibitors of

A series of pyrazolidine-3,5-dione and 5-hydroxy-1H-pyrazol-3(2H)-one inhibitors of Escherichia coli UDP-N-acetylenolpyruvyl glucosamine reductase (MurB) has been prepared. The 5-hydroxy-1H-pyrazol-3(2H)ones show low micromolar IC50 values versus E. coli MurB and submicromolar minimal inhibitory concentrations ( MIC) against Staphylococcus aureus GC 1131, Enterococcus faecalis GC 2242, Streptococcus pneumoniae GC 1894, and E. coli GC 4560 imp, a strain with increased outer membrane permeability. None of these compounds show antimicrobial activity against Candida albicans, a marker of eukaryotic toxicity. Moreover, these compounds inhibit peptidoglycan biosynthesis, as assessed by measuring the amount of soluble peptidoglycan produced by Streptococcus epidermidis upon incubation with compounds. A partial least squares projection to latent structures analysis shows that improving MurB potency and MIC values correlate with increasing lipophilicity of the C-4 substituent of the 5-hydroxy-1H-pyrazol-3(2H)-one core. Docking studies using FLO and PharmDock produced several binding orientations for these molecules in the MurB active site.

Over 195 4-alkyl and 4,4-dialkyl 1,2-bis(4-chlorophenyl)pyrazolidine-3,5-dione derivatives were synthesized, utilizing microwave accelerated synthesis, for evaluation as new inhibitors of bacterial cell wall biosynthesis. Many of them demonstrated good activity against MurB in vitro and low MIC values against Gram-positive bacteria, particularly penicillin-resistant Streptococcus pneumoniae (PRSP). Derivative 7l demonstrated antibacterial activity against both Gram-positive and Gram-negative bacteria. Derivatives 7f and 10a also demonstrated potent nanomolar Kd values in their binding to MurB.

Over 50 phenyl thiazolyl urea and carbamate derivatives were synthesized for evaluation as new inhibitors of bacterial cell-wall biosynthesis. Many of them demonstrated good activity against MurA and MurB and gram-positive bacteria including MRSA, VRE and PRSP. 3,4-Difluorophenyl 5-cyanothiazolylurea (3p) with clog P of 2.64 demonstrated antibacterial activity against both gram-positive and gram-negative bacteria.

ABSTRACT The naturally occurring mannopeptimycins (formerly AC98-1 through AC98-5) are a novel class of glycopeptide antibiotics that are active against a wide variety of gram-positive bacteria. The structures of the mannopeptimycins suggested that they might act by targeting cell wall biosynthesis, similar to other known glycopeptide antibiotics; but the fact that the mannopeptimycins retain activity against vancomycin-resistant organisms suggested that they might have a unique mode of action. By using a radioactive mannopeptimycin derivative bearing a photoactivation ligand, it was shown that mannopeptimycins interact with the membrane-bound cell wall precursor lipid II [C55-MurNAc-(peptide)-GlcNAc] and that this interaction is different from the binding of other lipid II-binding antibiotics such as vancomycin and mersacidin. The antimicrobial activities of several mannopeptimycin derivatives correlated with their affinities toward lipid II, suggesting that the inhibition of cell wall biosynthesis was primarily through lipid II binding. In addition, it was shown that mannopeptimycins bind to lipoteichoic acid in a rather nonspecific interaction, which might facilitate the accumulation of antibiotic on the bacterial cell surface.

A series of Muraymycin analogues was synthesized. These analogues showed excellent antimicrobial activity against gram-positive organisms. These analogues also showed excellent inhibitory activity against the target peptidoglycan biosynthesis enzyme MraY, the cell membrane associated transglycosylase responsible for the formation of Lipid II.

ABSTRACT Previous studies suggested that a Gly-containing branch of cell wall precursor [C 55 -MurNAc-(peptide)-GlcNAc], which is often referred to as lipid II, might serve as a nucleophilic acceptor in sortase-catalyzed anchoring of surface proteins in Staphylococcus aureus. To test this hypothesis, we first simplified the procedure for in vitro biosynthesis of Gly-containing lipid II by using branched UDP-MurNAc-hexapeptide isolated from the cytoplasm of Streptomyces spp. Second, we designed a thin-layer chromatography-based assay in which the mobility of branched but not linear lipid II is shifted in the presence of both sortase and LPSTG-containing peptide. These results and those of additional experiments presented in this study further suggest that lipid II indeed serves as a natural substrate in a sorting reaction.

Sixteen muraymycin derivatives 2-17 were synthesized based on selective reactions of the primary and secondary amino groups of muraymycin Cl (1) with isocyanates and aldehydes. Disubstituted derivatives 3-9 demonstrated no activity against either MraY or MurG at less than or equal to 100 mug/mL whereas mono substituted derivatives 11-17 demonstrated good inhibitory activity, well correlated with the lipophilicity of the substituent introduced. In particular, the activity of derivatives 13 and 14 was comparable to that of muraymycin C1 in this assay. (C) 2002 Elsevier Science Ltd. All rights reserved.

The muraymycins, a family of nucleoside-lipopeptide antibiotics, were purified from the extract of Streptomyces sp. LL-AA896. The antibiotics were purified by chromatographic methods and characterized by NMR spectroscopy, degradation studies, and mass spectrometry. The structures of 19 compounds were established. The muraymycins constitute a new antibiotic family whose core structure contains a glycosylated uronic acid derivative joined by an aminopropane group to a hexahydro-2-imino-4-pyrimidylglycyl residue (epicapreomycidine) containing dipeptide that is further extended by a urea-valine moiety. Members of this family show broad-spectrum in vitro antimicrobial activity against a variety of clinical isolates (MIC 2 to >64 mug/mL). The muraymycins inhibited peptidoglycan biosynthesis. The fatty acid substituent and the presence or absence of the amino sugar play important roles in biological activity. One of the most active compounds, muraymycin A1, demonstrated protection in vivo against Staphylococcus aureus infection in mice (ED50 1.1 mg/kg).

AbstractFor Abstract see ChemInform Abstract in Full Text.

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