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 2.B.5 The Macrocyclic Polyether Ionophore (MPI) Family
 
Macrocyclic polyethers, or crown compounds, are neutral synthetic compounds that form stable complexes with alkali metal ions and certain amino acids such as arginine. Because of their hydrophobic (or amphipathic) character, they can transport these metal ions as well as protons across biological membranes, thus dissipating ion gradients (Eisenman et al. 1973). Selectivity toward different cations varies with polyether ring size, the optimum being such that the cation just fits into the hole (Avilés-Moreno et al. 2018). The effects of the macrocyclic polyether 15-crown-5 on the ionic permeability of excitable membranes has been examined (Bogatskiĭ et al. 1984).
 
Ciguatoxins (CTX) and brevetoxins (BTX) are polycyclic ethereal compounds biosynthesized by the worldwide distributed planktonic and epibenthic dinoflagellates of the Gambierdiscus and Karenia genera, respectively. Ciguatera, evoked by CTXs, is a type of ichthyosarcotoxism, which involves a variety of gastrointestinal and neurological symptoms, while BTXs cause so-called neurotoxic shellfish poisoning (Shmukler and Nikishin 2017). They have a similar mechanism of action. These are the only molecules known to activate voltage-sensitive Na⁺-channels in mammals through a specific interaction with site 5 of its α-subunit which results in an increase in neuronal excitability, neurotransmitter release and impairment of synaptic vesicle recycling. Most marine ciguatoxins potentiate Nav channels, but a considerable number of them, such as gambierol and maitotoxin, have been shown to affect other ion channels. Although the extrinsic function of these toxins is probably associated with the function of a feeding deterrent, their intrinsic function is coupled with the regulation of photosynthesis via light-harvesting complex II and thioredoxin. Antagonistic effects of BTXs and brevenal may provide evidence of their participation as positive and negative regulators of this mechanism (Shmukler and Nikishin 2017).

There are many polycyclic polyether ionoporous anitmicrobial compounds. These compounds include Grisoixin (Gachon and Kergomard 1975), Emericid (Ninet et al. 1976), Alborixin (Gachon et al. 1976), Lasalocid (Minami et al. 2013) (see 2.B.14), Narasin (Riddell 2006), CP-54,883 (Cullen et al. 1987), Salinomycin (Antoszczak and Huczyński 2019), Maduramicin (Bharti et al. 2019), Monensin (see TC# 2.B.2), diterpenoids or pleuromutilins such as tiamulin, valnemulin, retapamulin and lefamulin (Paukner and Riedl 2017), Furazolidone (Zhuge et al. 2018), Tetronomycin (Keller-Juslén et al. 1982), Merrosamycins A & B (Zhuge et al. 2018), Terrosamycins A & B (Sproule et al. 2019) and Noboritomycins A & B (Keller-Juslén et al. 1978). Many of these compounds use a carrier-type mechanism to transport ions and occasionally other compounds across membranes (Gallimore 2009).

The generalized transport reaction catalyzed by MP family members is:

M+ (in) M+ (out)

References associated with 2.B.5 family:

Antoszczak, M. and A. Huczyński. (2019). Salinomycin and its derivatives - A new class of multiple-targeted "magic bullets". Eur J Med Chem 176: 208-227. 31103901
Avilés-Moreno, J.R., , G. Berden, , J. Oomens, , and B. Martínez-Haya,. (2018). Guanidinium/ammonium competition and proton transfer in the interaction of the amino acid arginine with the tetracarboxylic 18-crown-6 ionophore. Phys Chem Chem Phys 20: 4067-4073. 29354835
Bharti, H., A. Singal, M. Raza, P.C. Ghosh, and A. Nag. (2019). Ionophores as Potent Anti-malarials: A Miracle in the Making. Curr Top Med Chem 18: 2029-2041. 30499390
Bogatskiĭ, A.V., N.G. Luk''ianenko, T.A. Savenko, V.G. Vongaĭ, and E.I. Nazarov. (1984). [Effect of the macrocyclic polyether 15-crown-5 on the ionic permeability of excitable membranes]. Biull Eksp Biol Med 98: 165-168. 6087953
Cullen, W.P., W.D. Celmer, L.R. Chappel, L.H. Huang, H. Maeda, S. Nishiyama, R. Shibakawa, J. Tone, and P.C. Watts. (1987). CP-54,883 a novel chlorine-containing polyether antibiotic produced by a new species of Actinomadura: taxonomy of the producing culture, fermentation, physico-chemical and biological properties of the antibiotic. J Antibiot (Tokyo) 40: 1490-1495. 3693118
Eisenman, G., G. Szabo, S.G. McLaughlin, and S.M. Ciani. (1973). Molecular basis for the action of macrocyclic carriers on passive ionic translocation across lipid bilayer membranes. J. Bioenerg. 4: 93-148. 4717529
Gachon, P. and A. Kergomard. (1975). Grisorixin, an ionophorous antibiotic of the nigericin group. II. Chemical and structural study of grisorixin and some derivatives. J Antibiot (Tokyo) 28: 351-357. 1165221
Gachon, P., C. Farges, and A. Kergomard. (1976). Alborixin, a new antibiotic ionophore: isolation, structure, physical and chemical properties. J Antibiot (Tokyo) 29: 603-610. 950314
Gallimore, A.R. (2009). The biosynthesis of polyketide-derived polycyclic ethers. Nat Prod Rep 26: 266-280. 19177224
Keller-Juslén, C., H.D. King, M. Kuhn, H.R. Loosli, and A. von Wartburg. (1978). Noboritomycins A and B, new polyether antibiotics. J Antibiot (Tokyo) 31: 820-828. 711624
Keller-Juslén, C., H.D. King, M. Kuhn, H.R. Loosli, W. Pache, T.J. Petcher, H.P. Weber, and A. von Wartburg. (1982). Tetronomycin, a novel polyether of unusual structure. J Antibiot (Tokyo) 35: 142-150. 7076564
Minami, A., H. Oguri, K. Watanabe, and H. Oikawa. (2013). Biosynthetic machinery of ionophore polyether lasalocid: enzymatic construction of polyether skeleton. Curr Opin Chem Biol 17: 555-561. 23796908
Ninet, L., F. Benazet, H. Depaire, J. Florent, J. Lunel, D. Mancy, A. Abraham, J.R. Cartier, N. de Chezelles, C. Godard, M. Moreau, R. Tissier, and J.Y. Lallemand. (1976). Emericid, a new polyether antibiotic from Streptomyces hygroscopicus (DS 24 367). Experientia 32: 319-321. 1253897
Paukner, S. and R. Riedl. (2017). Pleuromutilins: Potent Drugs for Resistant Bugs-Mode of Action and Resistance. Cold Spring Harb Perspect Med 7:. 27742734
Riddell, F.G. (2006). Structure, conformation, and mechanism in the membrane transport of alkali metal ions by ionophoric antibiotics. Chirality 14: 121-125. 11835554
Shmukler, Y.B. and D.A. Nikishin. (2017). Ladder-Shaped Ion Channel Ligands: Current State of Knowledge. Mar Drugs 15:. 28726749
Sproule, A., H. Correa, A. Decken, B. Haltli, F. Berrué, D.P. Overy, and R.G. Kerr. (2019). Terrosamycins A and B, Bioactive Polyether Ionophores from sp. RKND004 from Prince Edward Island Sediment. Mar Drugs 17:. 31212620
Zhuge, L., Y. Wang, S. Wu, R.L. Zhao, Z. Li, and Y. Xie. (2018). Furazolidone treatment for Helicobacter Pylori infection: A systematic review and meta-analysis. Helicobacter 23: e12468. 29480532