Naphthyl Tetronic Acids as Multi‐Target Inhibitors of Bacterial Peptidoglycan Biosynthesis

Mansour, Tarek S.; Caufield, Craig E.; Rasmussen, Beth A.; Chopra, Rajiv; Krishnamurthy, Girija; Morris, Koi; Svenson, Kristine; Bard, Joel; Smeltzer, Claudia; Naughton, Shaughnessy; Antane, Schuyler; Yang, Youjun; Severin, Anatoly; Quagliato, Dominick A.; Petersen, Peter J.; Singh, Guy

doi:10.1002/cmdc.200700094

Cited by 42 publications

(21 citation statements)

References 33 publications

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“…A number of synthetic projects undertaken by the Wyeth group (12,119,201,212,234,395) were directed toward finding inhibitors of multiple enzymatic steps in the Mur pathway, with the idea that hitting multiple targets would lessen ultimate resistance selection. For many of these, the lead compound was discovered in a "one-pot" MurA-to-MurF screen (234), probably similar to those of Merck and Versicor.…”

Section: Murb To Murf Enzymes As Antibacterial Targetsmentioning

confidence: 99%

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Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,155

961

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SUMMARY The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort.

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Section: Murb To Murf Enzymes As Antibacterial Targetsmentioning

confidence: 99%

“…For many of these, the lead compound was discovered in a "one-pot" MurA-to-MurF screen (234), probably similar to those of Merck and Versicor. Hits from that screen were assayed against the individual enzymes, and leads were chosen for expansion.…”

Section: Murb To Murf Enzymes As Antibacterial Targetsmentioning

confidence: 99%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,155

961

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“…Several important binding site residues are also found to provide the basis for substrate discrimination against NADH. Importantly, a three-fragment strategy targeting three loci in the substrate channel should prove invaluable in designing new inhibitors against MurB from P. aeruginosa as has been demonstrated for EcMurB [46].…”

Section: Discussionmentioning

confidence: 99%

Substrate Channel Flexibility in Pseudomonas aeruginosa MurB Accommodates Two Distinct Substrates

et al. 2013

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Biosynthesis of UDP-N-acetylmuramic acid in bacteria is a committed step towards peptidoglycan production. In an NADPH- and FAD-dependent reaction, the UDP-N-acetylglucosamine-enolpyruvate reductase (MurB) reduces UDP-N-acetylglucosamine-enolpyruvate to UDP-N-acetylmuramic acid. We determined the three-dimensional structures of the ternary complex of Pseudomonas aeruginosa MurB with FAD and NADP+ in two crystal forms to resolutions of 2.2 and 2.1 Å, respectively, to investigate the structural basis of the first half-reaction, hydride transfer from NADPH to FAD. The nicotinamide ring of NADP+ stacks against the si face of the isoalloxazine ring of FAD, suggesting an unusual mode of hydride transfer to flavin. Comparison with the structure of the Escherichia coli MurB complex with UDP-N-acetylglucosamine-enolpyruvate shows that both substrates share the binding site located between two lobes of the substrate-binding domain III, consistent with a ping pong mechanism with sequential substrate binding. The nicotinamide and the enolpyruvyl moieties are strikingly well-aligned upon superimposition, both positioned for hydride transfer to and from FAD. However, flexibility of the substrate channel allows the non-reactive parts of the two substrates to bind in different conformations. A potassium ion in the active site may assist in substrate orientation and binding. These structural models should help in structure-aided drug design against MurB, which is essential for cell wall biogenesis and hence bacterial survival.

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“…Perdih et al predicted the benzene-1,3-dicarboxylic acid has an inhibitory activity against MurD and MurE ligases [16]. Mansour et al predicted the naphthyl tetronic acids as multi target inhibitors of bacterial peptidoglycan biosynthesis [17]. Tomasic et al predicted 5-benzylidenethiazolidin-4-one as multi target inhibitor, active against MurD to MurF ligases [18].…”

Section: Introductionmentioning

confidence: 98%

Homology modeling and docking analyses of M. leprae Mur ligases reveals the common binding residues for structure based drug designing to eradicate leprosy

Shanmugam

Natarajan

2011

J Mol Model

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Multi drug resistance capacity for Mycobacterium leprae (MDR-Mle) demands the profound need for developing new anti-leprosy drugs. Since most of the drugs target a single enzyme, mutation in the active site renders the antibiotic ineffective. However, structural and mechanistic information on essential bacterial enzymes in a pathway could lead to the development of antibiotics that targets multiple enzymes. Peptidoglycan is an important component of the cell wall of M. leprae. The biosynthesis of bacterial peptidoglycan represents important targets for the development of new antibacterial drugs. Biosynthesis of peptidoglycan is a multi-step process that involves four key Mur ligase enzymes: MurC (EC:6.3.2.8), MurD (EC:6.3.2.9), MurE (EC:6.3.2.13) and MurF (EC:6.3.2.10). Hence in our work, we modeled the three-dimensional structure of the above Mur ligases using homology modeling method and analyzed its common binding features. The residues playing an important role in the catalytic activity of each of the Mur enzymes were predicted by docking these Mur ligases with their substrates and ATP. The conserved sequence motifs significant for ATP binding were predicted as the probable residues for structure based drug designing. Overall, the study was successful in listing significant and common binding residues of Mur enzymes in peptidoglycan pathway for multi targeted therapy.

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Naphthyl Tetronic Acids as Multi‐Target Inhibitors of Bacterial Peptidoglycan Biosynthesis

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.

Cited by 42 publications

References 33 publications

Challenges of Antibacterial Discovery

Challenges of Antibacterial Discovery

Substrate Channel Flexibility in Pseudomonas aeruginosa MurB Accommodates Two Distinct Substrates

Homology modeling and docking analyses of M. leprae Mur ligases reveals the common binding residues for structure based drug designing to eradicate leprosy

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