Natural Polyether Ionophores and Their Pharmacological Profile

This review is devoted to the study of the biological activity of polyether ionophores produced by bacteria, unicellular marine algae, red seaweeds, marine sponges, and coelenterates. Biological activities have been studied experimentally in various laboratories, as well as data obtained using QSAR (Quantitative Structure–Activity Relationships) algorithms. According to the data obtained, it was shown that polyether toxins exhibit strong antibacterial, antimicrobial, antifungal, antitumor, and other activities. Along with this, it was found that natural polyether ionophores exhibit such properties as antiparasitic, antiprotozoal, cytostatic, anti-mycoplasmal, and antieczema activities. In addition, polyethers have been found to be potential regulators of lipid metabolism or inhibitors of DNA synthesis. Further study of the mechanisms of action and the search for new polyether ionophores and their derivatives may provide more effective therapeutic natural polyether ionophores for the treatment of cancer and other diseases. For some polyether ionophores, 3D graphs are presented, which demonstrate the predicted and calculated activities. The data presented in this review will be of interest to pharmacologists, chemists, practical medicine, and the pharmaceutical industry.


Introduction
Natural polyether ionophore antibiotics are amazing chemical structures that are potent antibiotics and belong to the larger family of naturally occurring ionophores. It is known that the term "ionophore", first used in 1967, refers to the ability of a molecule to bind a metal ion and facilitate its transport through cell membranes. This chemicalphysiological property has made polyether ionophores a useful tool in studying the mechanisms of cation transport and served as a rationale for their biological activity [1][2][3][4]. Polyether ionophores are a class of organic substances that are squalene derivatives with a regular occurrence of multiple C-O-C motifs, including the distinct families of the ladder polyethers and exhibiting a wide range of high biological activities [5][6][7]. However, according to the Nakanishi hypothesis, many marine polyether metabolites can be biosynthesized from polyunsaturated fatty acids [8,9]. This class of polyether compounds is produced by unicellular marine algae, red seaweeds, marine sponges, and coelenterates, or is accumulated by some marine organisms such as mollusks [10][11][12][13].
Marine polyether ionophores are also known as phycotoxins and are produced to a large extent by phytoplankton and, in particular, dinoflagellates and diatoms. These microalgae and cyanobacteria in aquatic ecosystems, due to the massive increase in their biomass, create a natural phenomenon known as harmful algal blooms [14][15][16]. Algal blooms in seas and lakes have a negative impact on aquatic ecosystems, given that many of the polyether metabolites are toxic, which destroy coastal flora and fauna and are fatal to humans and animals [17][18][19].
The review focuses on natural polyether compounds isolated from bacteria, cyanobacteria, dinoflagellates, fungi, and some marine invertebrates. Linear and cyclic polyether toxins are a class of natural compounds that exhibit a wide range of biological activities such as strong antitumor, antifungal, and antibacterial activities. A comparative characteristic of the pharmacological profile of the individual chemical structure of each polyether ionophore using the QSAR method is presented [20][21][22].

Polyether Metabolites Produced by Dinoflagellates
Okadaic acid is one of the first marine polyether metabolites that was discovered over 50 years ago. In the early 1970s, a series of food poisoning outbreaks in Japan are known to have led to the discovery of a new type of shellfish poisoning in Tokyo, Yokohama, and mussels and scallops harvested in Miyagi Prefecture [23][24][25][26][27][28][29][30]. Numerous studies of these mollusks have shown that these bivalves accumulate okadaic acid (1) and its derivatives (2)(3)(4)(5) [23]. It turned out that okadaic acid is a polyether compound derived from the fatty acid C38 [24].
of the polyether metabolites are toxic, which destroy coastal flora and fauna and are fatal to humans and animals [17][18][19].
The review focuses on natural polyether compounds isolated from bacteria, cyanobacteria, dinoflagellates, fungi, and some marine invertebrates. Linear and cyclic polyether toxins are a class of natural compounds that exhibit a wide range of biological activities such as strong antitumor, antifungal, and antibacterial activities. A comparative characteristic of the pharmacological profile of the individual chemical structure of each polyether ionophore using the QSAR method is presented [20][21][22].

Polyether Metabolites Produced by Dinoflagellates
Okadaic acid is one of the first marine polyether metabolites that was discovered over 50 years ago. In the early 1970s, a series of food poisoning outbreaks in Japan are known to have led to the discovery of a new type of shellfish poisoning in Tokyo, Yokohama, and mussels and scallops harvested in Miyagi Prefecture [23][24][25][26][27][28][29][30]. Numerous studies of these mollusks have shown that these bivalves accumulate okadaic acid (1) and its derivatives (2)(3)(4)(5) [23]. It turned out that okadaic acid is a polyether compound derived from the fatty acid C38 [24].
In addition, goniodomin A exhibits antiangiogenic activities via i reorganization in endothelial cells [50]. Goniodomin A as an inhibito with 97.9% confidence and its 3D graph is shown in Figure 5. In additio shows antifungal (92.2%) and antibacterial (90%) activities. Azaspiracids (7)(8)(9), AZAs) are a group of lipophilic polyether toxin noflagellates belonging to the genera Azadinium and Amphidoma and shellfish and tunicates that accumulate them [51][52][53][54]. The AZAs induc neurotoxic effects; however, the mechanism of action is still unknown [5 Marine polyether metabolites named pectenotoxins (PTXs, 10-16, Figure 6, predicted activity shown in Table 3, and 3D graph is shown group of toxins associated with diarrhetic shellfish (particularly sca yessoensis) poisoning (DSP) and are isolated from DSP toxin-producing d demonstrated by numerous studies that DSP toxins are produced by nophysis species, including D. acuta, D. fortii, D. acuminata, D. norvegica caudata [56][57][58][59], they are also produced by benthic species such as Proroce Thus, the PTXs cause severe acute diseases in humans, as these toxins are promote tumor development, and cause hepatocyte necrosis. In add known about the chronic toxicology of PTXs or the potential long-term fects [62,63].
Marine polyether metabolites named pectenotoxins (PTXs, 10-16, for structures see Figure 6, predicted activity shown in Table 3, and 3D graph is shown in Figure 7) are a group of toxins associated with diarrhetic shellfish (particularly scallop Patinopecten yessoensis) poisoning (DSP) and are isolated from DSP toxin-producing dinoflagellates. As demonstrated by numerous studies that DSP toxins are produced by several of the Dinophysis species, including D. acuta, D. fortii, D. acuminata, D. norvegica, D. mitra and D. caudata [56][57][58][59], they are also produced by benthic species such as Prorocentrum lima [60,61]. Thus, the PTXs cause severe acute diseases in humans, as these toxins are highly cytotoxic, promote tumor development, and cause hepatocyte necrosis. In addition, nothing is known about the chronic toxicology of PTXs or the potential long-term public health effects [62,63].  Figure 6. Marine polyether pectenotoxins, and prorocentin and gambierol.  The unique structure of a toxin named prorocentin (17) possessed all-tran epoxide, as well as the 6/6/6-trans-fused/spiro-linked polyether ring moieties, by the marine benthic dinoflagellate Prorocentrum lima, which is widespread in ters anywhere in the world [64]. Prorocentin exhibited inhibitory activity aga colon adenocarcinoma DLD-1 and human malignant melanoma RPMI7951 w ues of 16.7 and 83.6 µg/mL, respectively [64].
Gambierol (18) is a marine polycyclic ether toxin that is produced by the late Gambierdiscus toxicus and is a potent blocker of voltage-gated potassium ch 67]. Another analogue of gambierol named gambierone (19, seen in Figure 8) w from the cultured dinoflagellate Gambierdiscus belizeanus, as well as gambier methylgambierone (20), which were found in another species, the benthic di Gambierdiscus australes [68,69]. Potential antifungal polyether compounds calle acids A (21), B (22), C (23), and D (24, for structure see Figure 8) were isolated fr from the marine dinoflagellate Gambierdiscus toxicus [70]. The unique structure of a toxin named prorocentin (17) possessed all-trans trienes, an epoxide, as well as the 6/6/6-trans-fused/spiro-linked polyether ring moieties, is produced by the marine benthic dinoflagellate Prorocentrum lima, which is widespread in ocean waters anywhere in the world [64]. Prorocentin exhibited inhibitory activity against human colon adenocarcinoma DLD-1 and human malignant melanoma RPMI7951 with IC 50 values of 16.7 and 83.6 µg/mL, respectively [64].
A group of lipid soluble polyether compounds called ciguatoxins (CTXs, 25-27, structures seen in Figure 9) are potent ichthyotoxins produced by a toxic benthic dinoflagellate, Gambierdiscus toxicus [71][72][73]. The main toxin, named ciguatoxin, was first isolated from the liver of a moray eel caught off the coast of the Hawaiian Islands. This epiphytic G. toxicus dinoflagellate (see Figure 10) is the main source of toxins that accumulate in various fish species [74,75]. Ciguatera fish poisoning is a form of food poisoning caused by the consumption of varieties of toxic ciguatera fish species from tropical and subtropical waters [76][77][78]. A group of lipid soluble polyether compounds called ciguatoxins (CTXs, 25-27, structures seen in Figure 9) are potent ichthyotoxins produced by a toxic benthic dinoflagellate, Gambierdiscus toxicus [71][72][73]. The main toxin, named ciguatoxin, was first isolated from the liver of a moray eel caught off the coast of the Hawaiian Islands. This epiphytic G.toxicus dinoflagellate (see Figure 10) is the main source of toxins that accumulate in various fish species [74,75]. Ciguatera fish poisoning is a form of food poisoning caused by the consumption of varieties of toxic ciguatera fish species from tropical and subtropical waters [76][77][78].    A single-celled phytoplanktonic organism, the marine dinoflagellate G. toxicus, is found in tropical waters around the world. Maitotoxin (27 and 28, for structure see Figure 9, predicted activity shown in Table 4, and 3D graph seen in Figures 11 and 12) and related toxins accumulate in the food chain when predatory fish consume contaminated herbivorous reef fish. Maitotoxin accumulates mainly in the liver and internal organs of fish, but not in their flesh. Higher concentrations of toxins can be found in large carnivores such as barracuda, sea bass, amberjack, perch, and others [79,80].      showing the highest degree of confidence, more than 94%. Table 4. Predicted activity of lipophilic polyether toxins (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34).

No. Predicted Biological Activity, Pa *
A microscopic single-cell photosynthetic organism of the genus Karenia, K. brevis (see Figure 10b), is a marine dinoflagellate that is commonly found in the waters of the Gulf of Mexico and is responsible for the so-called Florida Red Tides (see Figures 13 and 14) that affect the Florida and Texas Gulf coasts of the United States and the nearby coasts of Mexico. Karenia brevis produces a set of potent neurotoxins, collectively called brevetoxins (PbTxs, 29-34, for structure see Figure 15, predicted activity shown in Table 4), that cause gastrointestinal and neurological problems in other organisms and are responsible for the massive death of marine organisms and seabirds [81][82][83].
Mar. Drugs 2022, 20, x 13 of 59 A microscopic single-cell photosynthetic organism of the genus Karenia, K. brevis (see Figure 10b), is a marine dinoflagellate that is commonly found in the waters of the Gulf of Mexico and is responsible for the so-called Florida Red Tides (see Figures 13 and 14) that affect the Florida and Texas Gulf coasts of the United States and the nearby coasts of Mexico. Karenia brevis produces a set of potent neurotoxins, collectively called brevetoxins (PbTxs, 29-34, for structure see Figure 15, predicted activity shown in Table 4), that cause gastrointestinal and neurological problems in other organisms and are responsible for the massive death of marine organisms and seabirds [81][82][83]. Figure 13. The red tide in Florida is a high concentration of naturally occurring marine dinoflagellates called Karenia brevis. These microalgae produce brevetoxins, powerful neurotoxins that can kill marine invertebrates, fish, animals, macroalgae, and can also be dangerous to humans. Figure 14. The red tide in Florida caused catastrophic consequences, and above all, it was the mass death of marine fish, animals, and marine invertebrates. The number of dead fish and animals is Figure 13. The red tide in Florida is a high concentration of naturally occurring marine dinoflagellates called Karenia brevis. These microalgae produce brevetoxins, powerful neurotoxins that can kill marine invertebrates, fish, animals, macroalgae, and can also be dangerous to humans. A microscopic single-cell photosynthetic organism of the genus Karenia, K. brevis (see Figure 10b), is a marine dinoflagellate that is commonly found in the waters of the Gulf of Mexico and is responsible for the so-called Florida Red Tides (see Figures 13 and 14) that affect the Florida and Texas Gulf coasts of the United States and the nearby coasts of Mexico. Karenia brevis produces a set of potent neurotoxins, collectively called brevetoxins (PbTxs, 29-34, for structure see Figure 15, predicted activity shown in Table 4), that cause gastrointestinal and neurological problems in other organisms and are responsible for the massive death of marine organisms and seabirds [81][82][83]. Figure 13. The red tide in Florida is a high concentration of naturally occurring marine dinoflagellates called Karenia brevis. These microalgae produce brevetoxins, powerful neurotoxins that can kill marine invertebrates, fish, animals, macroalgae, and can also be dangerous to humans. Figure 14. The red tide in Florida caused catastrophic consequences, and above all, it was the mass death of marine fish, animals, and marine invertebrates. The number of dead fish and animals is Figure 14. The red tide in Florida caused catastrophic consequences, and above all, it was the mass death of marine fish, animals, and marine invertebrates. The number of dead fish and animals is estimated at tens of thousands of tons. Red tides in Florida affect areas in southwest Florida including Palm Beach, Martin, St. Lucie, Glades, Hendry, Lee, and Okeechobee counties. The tourism business has been deeply affected because people do not want to be outdoors due to the strong smell and cough that the red tide causes. Fish kills and respiratory problems in humans can occur when microalgae cell levels reach 10,000 cells per liter, and cell concentrations as high as 2.5 million cells per liter have been found in some locations near the Sanibel Lighthouse. estimated at tens of thousands of tons. Red tides in Florida affect areas in southwest Florida includ ing Palm Beach, Martin, St. Lucie, Glades, Hendry, Lee, and Okeechobee counties. The tourism busi ness has been deeply affected because people do not want to be outdoors due to the strong smel and cough that the red tide causes. Fish kills and respiratory problems in humans can occur when microalgae cell levels reach 10,000 cells per liter, and cell concentrations as high as 2.5 million cells per liter have been found in some locations near the Sanibel Lighthouse. A marine toxin and complex polycyclic ether called brevisulcenal-F (35, for structure see Figure 16) was found in an extract of the dinoflagellate Karenia brevisulcata, which was dominant in the red tide of K. brevisulcata in Wellington Harbour, New Zealand. An extract of K. brevisulcata showed potent mouse lethality and cytotoxicity, and laboratory cultures of K. brevisulcata produced a range of novel lipid-soluble toxins [84]. Other polycyclic ether toxins, namely brevisulcenals A1 (36) and brevisulcatic acids (BSXs, 37-39, structures seen in Figure 17, and see 3D graph in Figure 18) produced by the red tide dinoflagellate K. brevisulcata, were the cause of a toxic incident that occurred in New Zealand [85]  A marine toxin and complex polycyclic ether called brevisulcenal-F (35, for structure see Figure 16) was found in an extract of the dinoflagellate Karenia brevisulcata, which was dominant in the red tide of K. brevisulcata in Wellington Harbour, New Zealand. An extract of K. brevisulcata showed potent mouse lethality and cytotoxicity, and laboratory cultures of K. brevisulcata produced a range of novel lipid-soluble toxins [84]. Other polycyclic ether toxins, namely brevisulcenals A1 (36) and brevisulcatic acids (BSXs, 37-39, structures seen in Figure 17, and see 3D graph in Figure 18) produced by the red tide dinoflagellate K. brevisulcata, were the cause of a toxic incident that occurred in New Zealand [85].    Two cytotoxic polyethers named gymnocin A (40) and B (41) were isolated from the notorious red tide dinoflagellate, Gymnodinium mikimotoi [86][87][88].
Ciguatoxins (42-45, for structures see Figure 19, and activity see in Table 5) are polyether toxins derived from marine dinoflagellates. Ciguatera fish poisoning (CFP) is currently the most common marine biotoxin food poisoning worldwide, associated with human consumption of circumtropical fish and marine invertebrates that are contaminated with ciguatoxins. Ciguatoxins are a potent sodium channel activator and contain neurotoxins that pose a health hazard at very low concentrations [89,90]. Two cytotoxic polyethers named gymnocin A (40) and B (41) were isolated from the notorious red tide dinoflagellate, Gymnodinium mikimotoi [86][87][88].
Ciguatoxins (42-45, for structures see Figure 19, and activity see in Table 5) are polyether toxins derived from marine dinoflagellates. Ciguatera fish poisoning (CFP) is currently the most common marine biotoxin food poisoning worldwide, associated with human consumption of circumtropical fish and marine invertebrates that are contaminated with ciguatoxins. Ciguatoxins are a potent sodium channel activator and contain neurotoxins that pose a health hazard at very low concentrations [89,90].

No. Predicted Biological
The karlotoxins are a class of amphidinol-like compounds (68-72, structures seen in Figure 25, predicted activity shown in Table 7, and 3D graph seen in Figure 26) produced by mixotrophic strains of the dinoflagellate Karlodinium veneficum (originally Gymnodinium veneficum), and Amphidinium sp. The karlotoxins have been reported to display a variety of interesting effects on biological systems, including cellular lysis, damage of fish gills, and immobilization of prey organisms. The cytolytic activity of the karlotoxins is modulated by membrane sterol composition, which has been proposed as a mechanism for K. veneficum avoiding autotoxicity. This dinoflagellate has been implicated in several fish kill events apparently caused by the damaging effects of the karlotoxins [109][110][111][112].  The karlotoxins are a class of amphidinol-like compounds (68-72, structures seen in Figure 25, predicted activity shown in Table 7, and 3D graph seen in Figure 26) produced by mixotrophic strains of the dinoflagellate Karlodinium veneficum (originally Gymnodinium veneficum), and Amphidinium sp. The karlotoxins have been reported to display a variety of interesting effects on biological systems, including cellular lysis, damage of fish gills, and immobilization of prey organisms. The cytolytic activity of the karlotoxins is modulated by membrane sterol composition, which has been proposed as a mechanism for K. veneficum avoiding autotoxicity. This dinoflagellate has been implicated in several fish kill events apparently caused by the damaging effects of the karlotoxins [109][110][111][112].   Figure 25. A class of amphidinol-like compounds named karlotoxins produced by mixotrophic strains of the dinoflagellate Karlodinium veneficum and several Amphidinium species. Figure 25. A class of amphidinol-like compounds named karlotoxins produced by mixotrophic strains of the dinoflagellate Karlodinium veneficum and several Amphidinium species. Table 7. Predicted activity of lipophilic polyether toxins (62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72).
Terrosamycins A (77, structure seen in Figure 30, predicted activity shown in Table  9, and 3D graph seen in Figure 31) and B (78), two polycyclic polyether natural products, were purified from the fermentation broth of Streptomyces sp. RKND004, isolated from Prince Edward Island sediment. Like other polyether ionophores, both compounds exhibited excellent antibiotic activity against Gram-positive pathogens. Interestingly, the terrosamycins also exhibited activity against two breast cancer cell lines [151]. Two polyether-type metabolites (79 and 80) were isolated from the marine-derived Streptomyces cacaoi and showed antimicrobial activity, while (80) also showed anticancer activity against Hela, PC-3, and A549 [152].
Terrosamycins A (77, structure seen in Figure 30, predicted activity shown in Table 9, and 3D graph seen in Figure 31) and B (78), two polycyclic polyether natural products, were purified from the fermentation broth of Streptomyces sp. RKND004, isolated from Prince Edward Island sediment. Like other polyether ionophores, both compounds exhibited excellent antibiotic activity against Gram-positive pathogens. Interestingly, the terrosamycins also exhibited activity against two breast cancer cell lines [151]. Two polyether-type metabolites (79 and 80) were isolated from the marine-derived Streptomyces cacaoi and showed antimicrobial activity, while (80) also showed anticancer activity against Hela, PC-3, and A549 [152].
Other antibiotics called salinomycin (82, 3D graph seen in Figure 32), SY-2 (84), and SY-9 (85) were produced by a strain of Streptomyces albus (ATCC 21838) [158][159][160]. Salinomycin is active against Gram-positive bacteria including mycobacteria and some filamentous fungi : Bacillus subtilis PCI 219, B. cereus IFO 3466, B. circulans 1170 3329 (83) is also an antibiotic polyether and is produced by a strain of Streptomyces aureofaciens. It differs from salinomycin in an extra methyl group in position 4. Narasin is active in vitro against Gram-positive bacteria, anaerobic bacteria, and fungi and is effective in protecting chickens from coccidial infections:  [161,162]. In addition, narasin is active against several viruses including vaccinia virus, herpes virus, type III poliovirus, transmissible gastroenteritis, Newcastle disease virus, and infectious bovine rhinotracheitis virus [162].  Two isomeric homologs of lasalocid A (86, structure seen in Figure 33, predicted activity shown in Table 10) and B (87) have been isolated from cultures of Streptomyces lasaliensis. The homolog B differs from lasalocid A in that at position 4 of the benzene ring, homolog B contains an ethyl group, and homolog A contains a methyl group [163,164]. Both homologues are known to exhibit anticoccidial activity [165].
Two isomeric homologs of lasalocid A (86, structure seen in Figure 33, predicted activity shown in Table 10) and B (87) have been isolated from cultures of Streptomyces lasaliensis. The homolog B differs from lasalocid A in that at position 4 of the benzene ring, homolog B contains an ethyl group, and homolog A contains a methyl group [163,164]. Both homologues are known to exhibit anticoccidial activity [165].   A polyether antibiotic named tetronomycin (88, 3D graph seen in Figure 34) and an acetylated derivative (89) were found in the extract of a strain of Streptomyces sp. nov. Tetronomycin sodium salt shows a broad antibiotic activity against all Gram-positive bacteria tested and is also active against several Mycoplasma laidlawii and Neisseria pharynges species. Activity against other Gram-negative bacteria is lacking as well as an inhibition of yeasts and filamentous fungi: Staphylococcus aureus, Streptococcus faecalis, Micrococcus lysodeikticus, Bacillus subtilis, Micrococcus luteus, and Clostridium pasteurianum [166]. Noboritomycins A (90) and B (91), two ionophoric polyethers, were isolated from a strain of Streptomyces noboritoensis. An unusual spiroketal system as well as a salicylic acid chromophore represent further remarkable elements. Noboritomycin A shows, in this respect, structural relationships to both salinomycin and lasalocid. Comparison of physicochemical data, in particular the interpretation of the 1H-and 13C-NMR spectra, revealed that noboritomycins A and B are structurally closely related, with noboritomycin B carrying an ethyl substituent on the aromatic ring in the place of a methyl group present in noboritomycin A. Both metabolites exhibit activity against Gram-positive bacteria Staphylococcus aureus, Micrococcus lysodeikticus, Micrococcus sp., Bacillus subtilis, Streptococcus faecalis, Sarcina lutea, Neisseria pharynges, Clostridican pasteurianum, and Mycoplasma laidlawii, and against Eimeria tenella (chicken coccidiosis) [167].
The molecular structure and the cation binding of nigericin (93), an antibiotic affecting ion transport and ATPase activity in mitochondria, has been detected in Streptomyces sp. The molecule is found to be like monensin, another antibiotic of similar properties [169]. Two years later, an antibiotic related to nigericin was named grisorixin (94), isolated from cultures of a strain of Streptomyces griseus [170] : 88 and 89) showing the highest degree of confidence, more than 92%.
Noboritomycins A (90) and B (91), two ionophoric polyethers, were isolated from a strain of Streptomyces noboritoensis. An unusual spiroketal system as well as a salicylic acid chromophore represent further remarkable elements. Noboritomycin A shows, in this respect, structural relationships to both salinomycin and lasalocid. Comparison of physico-chemical data, in particular the interpretation of the 1H-and 13C-NMR spectra, revealed that noboritomycins A and B are structurally closely related, with noboritomycin B carrying an ethyl substituent on the aromatic ring in the place of a methyl group present in noboritomycin A. Both metabolites exhibit activity against Gram-positive bacteria Staphylococcus aureus, Micrococcus lysodeikticus, Micrococcus sp., Bacillus subtilis, Streptococcus faecalis, Sarcina lutea, Neisseria pharynges, Clostridican pasteurianum, and Mycoplasma laidlawii, and against Eimeria tenella (chicken coccidiosis) [167].
The molecular structure and the cation binding of nigericin (93), an antibiotic affecting ion transport and ATPase activity in mitochondria, has been detected in Streptomyces sp. The molecule is found to be like monensin, another antibiotic of similar properties [169]. Two years later, an antibiotic related to nigericin was named grisorixin (94), isolated from cultures of a strain of Streptomyces griseus [170]. It shows microbial activity against Grampositive bacteria and fungi:  [171].
The polyether antibiotic, X-206 (95), was isolated from Streptomyces sp. strain K99-0413 and has shown potent antimalarial properties in vitro against drug-resistant Plasmodium falciparum [172][173][174]. The pandemic spread of new human pathogenic viruses, such as the current SARS-CoV-2, is a major health and social concern. Antibiotic X-206 has shown potent ability to inhibit SARS-CoV-2 replication and cytopathogenicity in cells. Thus, the antibiotic X-206 can be considered one of the reliable agents for the treatment and prevention of SARS-CoV-2 coronavirus [175]. An antibiotic polyether with anthelmintic properties, A204A (96), has been found in the culture of Streptomyces albus [176].
Septamycin (97) is a metal-complexing polyether antibiotic produced by a strain of Streptomyces hygroscopicus NRRL 5678. Septamycin possesses antiviral activity against Newcastle Disease and herpes simplex viruses. In addition, this antibiotic in vitro shows antimicrobial activity against: Staphylococcus aureus, Streptococcus pyogenes, Bacillus subtilis, B. stearothermophilus, Escherichia coli, and Clostridium pasteurianum [177]. The ionophores septamycin (97), salinomycin (82), and CP-82,009 were purified from fermentation broth of the Actinomadura sp. culture N742-34 [178,179]. The other two are polyether antibiotic K-41A (98, structure seen in Figure 35, predicted activity shown in Table 11) and its analogue K-41Am (99), with antibacterial activity against Gram-positive bacteria and coccidia and anti-HIV activity exhibited, produced by a marine-derived Streptomyces sp. SCSIO 01680 [180]. An antibiotic, macrocyclic lactone carbonic acid named sorangicin A (100) was found in the culture supernatant of the myxobacterium Sorangium (Polyangium) cellulosum strain An antibiotic, macrocyclic lactone carbonic acid named sorangicin A (100) was found in the culture supernatant of the myxobacterium Sorangium (Polyangium) cellulosum strain eel2. The antibiotic mainly works against Gram-positive bacteria, including mycobacteria, as well as Gram-negative bacteria, and yeast and mold are completely resistant to this antibiotic [181].
It is known that monensin A is a representative of a large group of natural polyether ionophore antibiotics and was discovered in 1967 by Agtarap and colleagues as a metabolite formed during the biosynthesis of Streptomyces cinnamonensis [182]. One of the monensin analogs is monensin C (101), which demonstrates activity against Gram-positive bacteria of the genera Micrococcus, Bacillus, and Staphylococcus [183,184].
Mar. Drugs 2022, 20, x 39 of 59 eel2. The antibiotic mainly works against Gram-positive bacteria, including mycobacteria, as well as Gram-negative bacteria, and yeast and mold are completely resistant to this antibiotic [181]. It is known that monensin A is a representative of a large group of natural polyether ionophore antibiotics and was discovered in 1967 by Agtarap and colleagues as a metabolite formed during the biosynthesis of Streptomyces cinnamonensis [182]. One of the monensin analogs is monensin C (101), which demonstrates activity against Gram-positive bacteria of the genera Micrococcus, Bacillus, and Staphylococcus [183,184].
An antibiotic called octacyclomycin (107) was found in the fermentation broth of Streptomyces sp. No. 82-85 and showed both cytocidal activity against B16 melanoma cells and antimicrobial activity against Gram-positive bacteria in vitro [189].
An antibiotic named nanchangmycin (108, structure seen in Figure 37, predicted activity shown in Table 12, and 3D graph seen in Figure 38) was produced by Streptomyces nanchangensis NS3226 [143]. It demonstrated cytotoxic activity against several cancer cell lines, being most active against HL-60 (human leukemia) and HCT-116 (human colon carcinoma) cell lines, presenting IC 50 and (IS) values: 0.0014 µM (30.0) and 0.0138 µM (3.0), respectively. On HCT-116, nigericin caused apoptosis and autophagy. Nigericin also showed activity against a panel of cancer-related kinases and inhibited both JAK3 and GSK-3β kinases in vitro and its binding affinities [190]. showed activity against a panel of cancer-related kinases and inhibited both JAK3 and GSK-3β kinases in vitro and its binding affinities [190].   Streptomyces scabrisporus NF3, an endophytic actinomycete, which was isolated from Amphipterygium adstringens in Mexico, exhibited the potential to produce diverse bioactive compounds, for instance, the antibacterial hitachimycin and the antitumoral alborixin (109) [191].
A polyether antibiotic marked as 6016 (110) was isolated from the culture of Streptomyces albus strain No. 6016. The antibiotic exhibited activity against Gram-positive bacteria including mycobacteria and was effective in the treatment of coccidiosis of fowl [192,193]. A polyether ionophore antibiotic named cationomycin (111) was isolated from extracts of Actinomadura NOV sp. [194], and endusamycin (112) was isolated from Streptomyces endus [195]. Streptomyces scabrisporus NF3, an endophytic actinomycete, which was isolated from Amphipterygium adstringens in Mexico, exhibited the potential to produce diverse bioactive compounds, for instance, the antibacterial hitachimycin and the antitumoral alborixin (109) [191].
A polyether antibiotic marked as 6016 (110) was isolated from the culture of Streptomyces albus strain No. 6016. The antibiotic exhibited activity against Gram-positive bacteria including mycobacteria and was effective in the treatment of coccidiosis of fowl [192,193]. A polyether ionophore antibiotic named cationomycin (111) was isolated from extracts of Actinomadura NOV sp. [194], and endusamycin (112) was isolated from Streptomyces endus [195].
An antibiotic named mutalomycin (113) is a new metal-complexing polyether antibiotic produced by a strain of Streptomyces mutabilis NRRL 8088. Mutalomycin contains six heterocyclic rings and is structurally related to nigericin. The metabolite is active against Gram-positive bacteria and Eimeria tenella (chicken coccidiosis) [186]. Lasalocid metal (114) was isolated from Streptomyces lasaliensis. Crystal structures of lasalocid acid barium, silver, and strontium salts were determined. The monomeric unit of lasalocid thallium salt is stabilized by strong, intramolecular aryl-Tl type-metal half sandwich bonding interactions. Homologs of lasalocid acid were also described [196][197][198].
Antibiotics 27C6 (115, for structure see Figure 39, predicted activity shown in Table  12) and K-41 (116), carboxylic polyether compounds, were isolated from Leclercia adecarboxylata, the strain KP-27C6, and Streptomyces hygroscopicus K41, respectively. Both molecules exhibited antibacterial activity against Gram-positive bacteria, anti-coccidal activity, and delayed toxicity for poultry in vivo [199]. The structure of CP-96,797 (117), a polyether antibiotic, is related to K-41A and produced by Streptomyces sp. [200]. An antibiotic named mutalomycin (113) is a new metal-complexing polyether antibiotic produced by a strain of Streptomyces mutabilis NRRL 8088. Mutalomycin contains six heterocyclic rings and is structurally related to nigericin. The metabolite is active against Gram-positive bacteria and Eimeria tenella (chicken coccidiosis) [186]. Lasalocid metal (114) was isolated from Streptomyces lasaliensis. Crystal structures of lasalocid acid barium, silver, and strontium salts were determined. The monomeric unit of lasalocid thallium salt is stabilized by strong, intramolecular aryl-Tl type-metal half sandwich bonding interactions. Homologs of lasalocid acid were also described [196][197][198].
An antibiotic named octacyclomycin (118) was found in the culture broth of Streptomyces sp. No. 82-85 [201] and is also produced by Actinoallomurus sp. ID14582 [202]. An antibiotic marked W341C (119) is a monocarboxylic polyether metabolite with anti-coccidal properties produced by Streptomyces sp. W341, and it demonstrated the ability of W341C to induce potassium loss in Bacillus subtilis and Streptococcus agalactiae and promote potassium uptake into Escherichia coli [203]. An antibiotic named octacyclomycin (118) was found in the culture broth of Streptomyces sp. No. 82-85 [201] and is also produced by Actinoallomurus sp. ID14582 [202]. An antibiotic marked W341C (119) is a monocarboxylic polyether metabolite with anti-coccidal properties produced by Streptomyces sp. W341, and it demonstrated the ability of W341C to induce potassium loss in Bacillus subtilis and Streptococcus agalactiae and pro- The culture broth of an isolate, Streptomyces sp. CS684, showed antibacterial activity on methicilin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Among purified substances from the organism, CSU-1, which is active against MRSA and VRE, is identified as laidlomycin (120) [204].
A polyether antibiotic labeled CP-84,657 (121, structure seen in Figure 40 and activity prediction shown in Table 13) was isolated by solvent extraction from the fermentation broth of Actinomadura sp. (ATCC 53708). This antibiotic is among the most potent anti-coccidal agents known, effectively controlling the Eimeria species that are the major causative agents of chicken coccidiosis at doses of 5 Mg/kg or less in feed. It is also active in vitro against certain Gram-positive bacteria, as well as the spirochete, Treponema hyodysenteriae [205]. Another antibiotic ionophore, CP-54,883 (122), the molecule of which contains a polyether ring network and side chain terminated by an aromatic ring containing a phenoxy and two chlorine substituents, was found in the fermentation broth of Actinomadura routienii [206], and an antibiotic ionophore CP-80219 (123) was found in the fermentation broth of Streptomyces hygroscopicus ATCC 53626 [207]. The culture broth of an isolate, Streptomyces sp. CS684, showed antibacterial activity on methicilin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Among purified substances from the organism, CSU-1, which is active against MRSA and VRE, is identified as laidlomycin (120) [204].
A polyether antibiotic labeled CP-84,657 (121, structure seen in Figure 40 and activity prediction shown in Table 13) was isolated by solvent extraction from the fermentation broth of Actinomadura sp. (ATCC 53708). This antibiotic is among the most potent anticoccidal agents known, effectively controlling the Eimeria species that are the major causative agents of chicken coccidiosis at doses of 5 Mg/kg or less in feed. It is also active in vitro against certain Gram-positive bacteria, as well as the spirochete, Treponema hyodysenteriae [205]. Another antibiotic ionophore, CP-54,883 (122), the molecule of which contains a polyether ring network and side chain terminated by an aromatic ring containing a phenoxy and two chlorine substituents, was found in the fermentation broth of Actinomadura routienii [206], and an antibiotic ionophore CP-80219 (123) was found in the fermentation broth of Streptomyces hygroscopicus ATCC 53626 [207]. Grisorixin (124) is an ionophorous antibiotic of the nigericin group isolated from cultures of a strain of Streptomyces griseus. It shows activity against Gram-positive bacteria and fungi but is also very toxic [208].
An antibiotic labeled SF-2487 (125) was isolated from a culture broth of Actinomadura sp. SF2487. It showed moderate activity against Gram-positive bacteria, but no activity against Gram-negative bacteria. SF-2487 exhibited in vitro antiviral activity against influenza virus [209]. Another antibiotic labeled X-14931A (126) was isolated from a culture of Streptomyces sp. X-14931. Antibiotic X-14931A showed in vitro activity against Grampositive microorganisms and yeasts. It was also active against mixed Eimeria infection in chickens and exhibited activity in the rumen growth [210].
Two polyether ionophores, X-14873A (127, structure seen in Figure 41, predicted activity shown in Table 14) and X-14873H (128, 3D graph seen in Figure 42) were isolated from the fermentation of Streptomyces sp. X-14873 (ATCC31679). Antibiotic X-14873A was mainly active against Gram-positive bacteria, and X-14873H, the descarboxyl derivative of X-14873A, was also active against Gram-positive bacteria [211].     An antibiotic named noboritomycin (129) was isolated from Streptomyces noboritoensis. It was a polyether ionophore possessing two carboxylic acid functions on the carbon backbone, namely a free acid and an additional carboxylic acid ethyl ester group. This antibiotic was active against a wide range of Gram-positive bacteria [212]. The antibiotic 6-chloronoboritomycin (130) was isolated from S. malachitofuscus. It was active against Gram-positive bacteria and some anaerobes. In addition, it exhibited in vitro activity against several strains of Treponema hyodysenteriae, a causal agent of swine dysentery [213].
Antibiotic CP-82009 (131) was isolated by solvent extraction from the fermentation broth of Actinomadura species (specimen of this species seen in Figure 43). It exhibited activity against Gram-positive bacteria, as well as the spirochete Treponema hyodysenteriae [214]. An antibiotic named abierixin (132) was isolated from Streptomyces albus. It exhibited weak activity against Gram-positive bacteria [215].
An antibiotic named noboritomycin (129) was isolated from Streptomyces noboritoen It was a polyether ionophore possessing two carboxylic acid functions on the carbon ba bone, namely a free acid and an additional carboxylic acid ethyl ester group. This anti otic was active against a wide range of Gram-positive bacteria [212]. The antibiotic 6-ch ronoboritomycin (130) was isolated from S. malachitofuscus. It was active against Gra positive bacteria and some anaerobes. In addition, it exhibited in vitro activity agai several strains of Treponema hyodysenteriae, a causal agent of swine dysentery [213].
Antibiotic CP-82009 (131) was isolated by solvent extraction from the fermentati broth of Actinomadura species (specimen of this species seen in Figure 43). It exhibit activity against Gram-positive bacteria, as well as the spirochete Treponema hyodysenter [214]. An antibiotic named abierixin (132) was isolated from Streptomyces albus. It exhibit weak activity against Gram-positive bacteria [215]. A potent polyether ionophore antibiotic named maduramicin (133, structure seen Figure 44, and activity shown in Table 14) produced by Actinomadura rubra and Acti madura yumaensis NRRL12515 showed anthelmintic properties and is an antiprotoz agent used in veterinary medicine to prevent coccidiosis [216,217]. A potent polyether ionophore antibiotic named maduramicin (133, structure seen in Figure 44, and activity shown in Table 14) produced by Actinomadura rubra and Actinomadura yumaensis NRRL12515 showed anthelmintic properties and is an antiprotozoal agent used in veterinary medicine to prevent coccidiosis [216,217] An interesting antibiotic called lenoremycin (134) that demonstrated antimicrobial activity (up to 60 µM), cancer cell line cytotoxicity (up to 20 µM), and displayed antibacterial and antifungal activities, is produced by Streptomyces sp. RM-14-6 [218].
A polyether antibiotic, kijimicin (137, 3D graph seen in Figure 45) was found in the culture nitrate of Actinomadura sp. MI215-NF3, which was isolated from a soil sample collected at Bunkyo-ku, Tokyo, Japan. The antibiotic showed higher anticoccidial activity than monensin or salinomycin [221,222]. An interesting antibiotic called lenoremycin (134) that demonstrated antimicrobial activity (up to 60 µM), cancer cell line cytotoxicity (up to 20 µM), and displayed antibacterial and antifungal activities, is produced by Streptomyces sp. RM-14-6 [218].
A polyether antibiotic, kijimicin (137, 3D graph seen in Figure 45) was found in the culture nitrate of Actinomadura sp. MI215-NF3, which was isolated from a soil sample collected at Bunkyo-ku, Tokyo, Japan. The antibiotic showed higher anticoccidial activity than monensin or salinomycin [221,222]. Actinomycete Actinomadura sp. produced the antibiotic cationomycin (138) and its biosynthesis has been studied [223,224].

Structure-Activity Relationships and Biological Activities of Natural Polyether Ionophores
It is known that the chemical structure of both natural and synthetic molecules predetermines biological activity, which makes it possible to analyze the structure-activity relationships (SARs). Such a wise idea was first proposed by Brown and Fraser more than 150 years ago, in 1868 [228]; although, according to other sources, SAR originates from the field of toxicology, according to which Cros, in 1863, determined the relationship between the toxicity of primary aliphatic alcohols and their solubility in water [229]. More than 30 years later, Richet in 1893 [230], Meyer in 1899 [231], and Overton in 1901 [232] separately found a linear correlation between lipophilicity and biological effects. By 1935, Hammett [233,234] presented a method of accounting for the effect of substituents on reaction mechanisms using an equation that considered two parameters, namely the substituent constant and the reaction constant. Complementing Hammett's model, Taft proposed, in 1956, an approach for separating the polar, steric, and resonance effects of substituents in aliphatic compounds [235]. Combining all previous developments, Hansch and Fujita laid out the mechanistic basis for the development of the QSAR method [236], and the linear Hansch equation and Hammett's electronic constants are detailed in the book by Hansch and Leo published in 1995 [237]. Actinomycete Actinomadura sp. produced the antibiotic cationomycin (138) and its biosynthesis has been studied [223,224].

Structure-Activity Relationships and Biological Activities of Natural Polyether Ionophores
It is known that the chemical structure of both natural and synthetic molecules predetermines biological activity, which makes it possible to analyze the structure-activity relationships (SARs). Such a wise idea was first proposed by Brown and Fraser more than 150 years ago, in 1868 [228]; although, according to other sources, SAR originates from the field of toxicology, according to which Cros, in 1863, determined the relationship between the toxicity of primary aliphatic alcohols and their solubility in water [229]. More than 30 years later, Richet in 1893 [230], Meyer in 1899 [231], and Overton in 1901 [232] separately found a linear correlation between lipophilicity and biological effects. By 1935, Hammett [233,234] presented a method of accounting for the effect of substituents on reaction mechanisms using an equation that considered two parameters, namely the substituent constant and the reaction constant. Complementing Hammett's model, Taft proposed, in 1956, an approach for separating the polar, steric, and resonance effects of substituents in aliphatic compounds [235]. Combining all previous developments, Hansch and Fujita laid out the mechanistic basis for the development of the QSAR method [236], and the linear Hansch equation and Hammett's electronic constants are detailed in the book by Hansch and Leo published in 1995 [237]. Some well-known computer programs can, with some degree of reliability, estimate the pharmacological activity of organic molecules isolated from natural sources or synthesized compounds [238][239][240]. It is known that classical SAR methods are based on the analysis of (quantitative) structure-activity relationships for one or more biological activities, using organic compounds belonging to the same chemical series as the training set [241]. The computer program PASS, which has been continuously updating and improving for the past thirty years [20], is based on the analysis of a heterogeneous training set including information about more than 1.3 million known biologically active compounds with data on ca. 10,000 biological activities [20,22]. Chemical descriptors implemented in PASS, which reflect the peculiarities of ligand-target interactions and the original realization of the Bayesian approach for elucidation of structure-activity relationships, provide the average accuracy and predictivity for several thousand biological activities equal to about 96% [20,21]. In several comparative studies, it was shown that PASS outperforms, in predictivity, some other recently developed methods for the estimation of biological activity profiles [20][21][22]. Freely available via the Internet, the PASS Online web service [242] is used by more than thirty thousand researchers from almost a hundred countries to determine the most promising biological activities for both natural and synthetic compounds [243][244][245][246][247]. To reveal the hidden pharmacological potential of the natural substances, we have successfully used PASS for the past fifteen years [248][249][250][251][252][253][254].

Conclusions
In connection with the intensive development of information technology in the last decade, a lot of computer programs have appeared that use algorithms to determine the biological activity of various natural and synthetic molecules. Many of them, as a rule, are not effective enough for these purposes. However, there are programs that have proven their effectiveness for several decades. The data on the biological activity of natural polyether ionophores given in this review were obtained both experimentally and using PASS. The data comparison shows that natural polyether ionophores exhibit strong antitumor, antifungal, antibacterial, and antimicrobial activities, among many other activities. The presented data may be of interest to specialists in various fields of science such as organic chemistry and molecular biology; however, these data are of the greatest interest in a practical use for pharmacologists, physicians, and in applied medicine.
Funding: This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.