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 Na_v 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).