Polyether ionophores

Dutton, Christopher J.; Banks, B. J.; COOPER, C. B.

doi:10.1039/np9951200165

Cited by 155 publications

(115 citation statements)

References 13 publications

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“…The 1 H, 13 C, DEPT, and HSQC spectra of 1.264-B showed 49 carbon signals for 11 methyl groups, 4 methoxy groups, 9 methylenes, 6 methines, 11 oxymethines, 1 dioxymethine, and 7 quaternary carbons (including one carboxyl carbon [␦ C 181.35]). The planar structure of 1.264-B was established by the comparison of the 13 C-NMR spectrum to that of etheromycin (40) and by further two-dimensional NMR (2D-NMR) analysis (KEY 1 H-1 H COSY, 1 H-13 C HMBC; see Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Polyether ionophores (Fig. 1) are a unique class of type I polyketides with a high degree of promise for the control of drug-resistant bacteria and parasites, and they have been widely used as effective veterinary drugs and food additives in animal husbandry (13). These molecules also show a broad spectrum of bioactivity, including antifungal, antiviral, antitumor, herbicidal, and anti-inflammatory activity, as well as effects on the central nervous system (CNS) and immunoregulatory systems (24).…”

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Genetic Screening Strategy for Rapid Access to Polyether Ionophore Producers and Products in Actinomycetes

Wang

Ning

et al. 2011

Appl Environ Microbiol

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Polyether ionophores are a unique class of polyketides with broad-spectrum activity and outstanding potency for the control of drug-resistant bacteria and parasites, and they are produced exclusively by actinomycetes. A special epoxidase gene encoding a critical tailoring enzyme involved in the biosynthesis of these compounds has been found in all five of the complete gene clusters of polyether ionophores published so far. To detect potential producer strains of these antibiotics, a pair of degenerate primers was designed according to the conserved regions of the five known polyether epoxidases. A total of 44 putative polyether epoxidase gene-positive strains were obtained by the PCR-based screening of 1,068 actinomycetes isolated from eight different habitats and 236 reference strains encompassing eight major families of Actinomycetales. The isolates spanned a wide taxonomic diversity based on 16S rRNA gene analysis, and actinomycetes isolated from acidic soils seemed to be a promising source of polyether ionophores. Four genera were detected to contain putative polyether epoxidases, including Micromonospora, which has not previously been reported to produce polyether ionophores. The designed primers also detected putative epoxidase genes from diverse known producer strains that produce polyether ionophores unrelated to the five published gene clusters. Moreover, phylogenetic and chemical analyses showed a strong correlation between the sequence of polyether epoxidases and the structure of encoded polyethers. Thirteen positive isolates were proven to be polyether ionophore producers as expected, and two new analogues were found. These results demonstrate the feasibility of using this epoxidase gene screening strategy to aid the rapid identification of known products and the discovery of unknown polyethers in actinomycetes.Programs aimed at the discovery of new secondary metabolites with interesting biological activities from microbial sources have found an impressive number of compounds during the past 50 years. Actinomycetes represent one of the most prolific microbial sources for the discovery of bioactive metabolites (5, 6), many of which are produced by polyketide synthase (PKS) systems (6, 42). Polyether ionophores (Fig.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Genetic Screening Strategy for Rapid Access to Polyether Ionophore Producers and Products in Actinomycetes

Wang

Ning

et al. 2011

Appl Environ Microbiol

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“…Coccidiosis is not limited to the poultry industry, and some Eimeria species can also affect cattle, sheep, and pigs; they thus constitute a potential threat for other intensive livestock industries. The anticoccidial drugs dominating the market in recent years for the treatment of avian Eimeria have been polyether ionophores (17). The advent of drug resistance and the limited efficacy of current drugs mean that identification of new drug targets and finding agents to exploit them are urgently required.…”

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Identification of Lead Compounds Targeting the Cathepsin B-Like Enzyme of Eimeria tenella

Schaeffer

Schroeder²,

Heckeroth³

et al. 2012

Antimicrob Agents Chemother

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Cysteine peptidases have been implicated in the development and pathogenesis of Eimeria. We have identified a single-copy cathepsin B-like cysteine peptidase gene in the genome database of Eimeria tenella (EtCatB). Molecular modeling of the predicted protein suggested that it differs significantly from host enzymes and could be a good drug target. EtCatB was expressed and secreted as a soluble, active, glycosylated mature enzyme from Pichia pastoris. Biochemical characterization of the recombinant enzyme confirmed that it is cathepsin B-like. Screening of a focused library against the enzyme identified three inhibitors (a nitrile, a thiosemicarbazone, and an oxazolone) that can be used as leads for novel drug discovery against Eimeria. The oxazolone scaffold is a novel cysteine peptidase inhibitor; it may thus find widespread use.

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“…It is well-known that cation carriers (cationophores) can serve as antibiotics and toxins 5,6 , and it seems likely that anion carriers might also show useful biological activity. However, suitable anionophores have only recently become available [7][8][9][10] , and the nature of their biological effects is still in question.…”

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Efficient, non-toxic anion transport by synthetic carriers in cells and epithelia

Valkenier

Judd³

et al. 2015

Nature Chem

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The transport of anions across cell membranes has become an important goal for supramolecular chemistry [1][2][3][4] . It is well-known that cation carriers (cationophores) can serve as antibiotics and toxins 5,6 , and it seems likely that anion carriers might also show useful biological activity. However, suitable anionophores have only recently become available 7-10 , and the nature of their biological effects is still in question. A particular hope is that anionophores might be used to replace the activity of endogenous anion channels which are missing or defective 11,2 . Such deficiencies underlie a number of medical conditions including Best disease, Startle disease, Bartter's syndrome and, most notably, the widespread lifeshortening genetic disease cystic fibrosis (CF) 12,13 .If anionophores are to be used to treat these "channelopathies", it must be shown that they can be delivered to cells in sufficient quantities to produce substantial effects, of the same order of magnitude as endogenous anion channels, and that these quantities are not toxic to the cells. However, while a wide variety of anionophores have been studied in synthetic membranes (principally large unilamellar vesicles, or LUVs), the range of systems subjected to biological investigations is still quite limited. Moreover, from the point of view of CF treatment, the results thus far have been mixed. On the positive side, a few systems have been tested in whole cells, epithelia or (in one case) genetically modified mice 14 , using electrophysiological methods such as patch-clamp and Ussing chamber, and shown to induce anion conduction without obvious toxic effects. These anionophores include synthetic 3 peptides conceptually related to natural anion channels 11,[15][16][17] , as well as the steroid-based system 1 from the authors' laboratory 18 , and other small organic molecules 14,19,20 .Less encouragingly, a number of molecules showing anion transport in LUVs have tested positive for anti-cancer cytotoxicity (potentially valuable, but incompatible with CF treatment) 8,[21][22][23][24][25] . Many of these systems, including the well-studied prodigiosin 2 26 , transport protons as well as anions 8,[21][22][23] . Intracellular acidification can lead to apoptosis 26 , so in these cases proton transport could underlie toxicity. On the other hand, a recent study on calixpyrroles 3 suggested that anion transport as such could be cytotoxic 25 . As the transport activity of 3 was only weak, this raises the concern that powerful anionophores might be highly toxic and thus unsuitable for CF treatment. Thus far the only biological testing of these "1,5-diaxial" systems has been the early study on 1, referred to above 18 . The assay involved the application of 1 to the apical membrane of oriented Madin Darby canine kidney cell (MDCK) epithelia, mounted in an Ussing chamber, and measurement of the resulting electrical current caused by Cl − transport. The methodology is well-established, but not so convenient for screening large numbers of compounds.Mor...

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Polyether ionophores

Cited by 155 publications

References 13 publications

Genetic Screening Strategy for Rapid Access to Polyether Ionophore Producers and Products in Actinomycetes

Genetic Screening Strategy for Rapid Access to Polyether Ionophore Producers and Products in Actinomycetes

Identification of Lead Compounds Targeting the Cathepsin B-Like Enzyme of Eimeria tenella

Efficient, non-toxic anion transport by synthetic carriers in cells and epithelia

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