Transport of the antibacterial agent (6S)-6-fluoroshikimate and other shikimate analogues by the shikimate transport system of Escherichia coli

Jude, David A.; Ewart, C D C; Thain, J L; Davies, Gareth; Nichols, Wright W.

doi:10.1016/0005-2736(95)00295-2

Cited by 10 publications

(7 citation statements)

References 12 publications

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“…This resistance correlates with a reduced ability to take up shikimate and has been mapped at or near shiA, which is one of at least two loci that determine shikimate uptake in E. coli [102]. Other shikimate-like inhibitors might suffer from the same problems, making altering modes of entry or "non-shikimate"-like inhibitors more promising strategies.…”

Section: Development Of Resistance To Inhibitorsmentioning

confidence: 99%

The Shikimate Pathway and Its Branches in Apicomplexan Parasites

et al. 2002

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The shikimate pathway is essential for production of a plethora of aromatic compounds in plants, bacteria, and fungi. Seven enzymes of the shikimate pathway catalyze sequential conversion of erythrose 4-phosphate and phosphoenol pyruvate to chorismate. Chorismate is then used as a substrate for other pathways that culminate in production of folates, ubiquinone, napthoquinones, and the aromatic amino acids tryptophan, phenylalanine, and tyrosine. The shikimate pathway is absent from animals and present in the apicomplexan parasites Toxoplasma gondii, Plasmodium falciparum, and Cryptosporidium parvum. Inhibition of the pathway by glyphosate is effective in controlling growth of these parasites. These findings emphasize the potential benefits of developing additional effective inhibitors of the shikimate pathway. Such inhibitors may function as broad-spectrum antimicrobial agents that are effective against bacterial and fungal pathogens and apicomplexan parasites.

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Section: Development Of Resistance To Inhibitorsmentioning

confidence: 99%

The Shikimate Pathway and Its Branches in Apicomplexan Parasites

et al. 2002

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“…The shikimate pathway is essential to bacteria, fungi, plants, and parasites but is not used in mammals (1,2), making the enzymes involved in this pathway attractive targets for the development of broad spectrum antibiotic drugs (3)(4)(5)(6) and herbicides (7). The pathway in Plasmodium, Toxoplasma, Cryptosporidium, and Eimeria parasites has attracted attention recently (1, 2) but also holds promise for the development of drugs to inhibit the growth of fungi and bacteria (8).…”

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confidence: 99%

The 2.3-Å Crystal Structure of the Shikimate 5-Dehydrogenase Orthologue YdiB from Escherichia coli Suggests a Novel Catalytic Environment for an NAD-dependent Dehydrogenase

Benach

Lee

Edstrom

et al. 2003

Journal of Biological Chemistry

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We present here the 2.3-Å crystal structure of the Escherichia coli YdiB protein, an orthologue of shikimate 5-dehydrogenase. This enzyme catalyzes the reduction of 3-dehydroshikimate to shikimate as part of the shikimate pathway, which is absent in mammals but required for the de novo synthesis of aromatic amino acids, quinones, and folate in many other organisms. In this context, the shikimate pathway has been promoted as a target for the development of antimicrobial agents. The crystal structure of YdiB shows that the protomer contains two ␣/␤ domains connected by two ␣-helices, with the N-terminal domain being novel and the C-terminal domain being a Rossmann fold. The NAD ؉ cofactor, which co-purified with the enzyme, is bound to the Rossmann domain in an elongated fashion with the nicotinamide ring in the pro-R conformation. Its binding site contains several unusual features, including a cysteine residue in close apposition to the nicotinamide ring and a clamp over the ribose of the adenosine moiety formed by phenylalanine and lysine residues. The structure explains the specificity for NAD versus NADP in different members of the shikimate dehydrogenase family on the basis of variations in the amino acid identity of several other residues in the vicinity of this ribose group. A cavity lined by residues that are 100% conserved among all shikimate dehydrogenases is found between the two domains of YdiB, in close proximity to the hydride acceptor site on the nicotinamide ring. Shikimate was modeled into this site in a geometry such that all of its heteroatoms form high quality hydrogen bonds with these invariant residues. Their strong conservation in all orthologues supports the possibility of developing broad spectrum inhibitors of this enzyme. The nature and disposition of the active site residues suggest a novel reaction mechanism in which an aspartate acts as the general acid/base catalyst during the hydride transfer reaction.

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“…The first efficacious shikimate pathway enzyme inhibitor with antimicrobial activity was (6S) -6-fluoroshikimate [77] , thought to inhibit p -aminobenzoic acid generation [78] , which serves as a substrate for downstream folate biosynthesis [79] . However, mutations in mechanisms of drug uptake occurred causing the rapid development of resistance specific to (6S) -6-fluoroshikimate [80,81] .…”

Section: Drug Development Based On the Shikimate Pathwaymentioning

confidence: 99%