Polyether Antibiotic Ionophores

The polyether ionophore class of antibiotics includes lasalocid, maduramicin, monensin, narasin, salinomycin, and semduramicin. These dmgs are used exclusively in 

INN lUPAC Name, Molecular Formula, and CAS Registry No. Chemical Structure P a 

Chloramphenicol 2,2-Dichloro-iV-[1,3-dihydroxy-l -(4-nitrophenyl)propan-2-yl] acetamide C11H12CI2N2O5 OH NH CHCI2 1 T CH2OH 0 N/A  

Polyether ionophores (Table 1.10) have a distinctly different mode of action from therapeutic antibiotics. 

6-[7i -[55 -ethyl-5-(5R-Ethyltetrahydro-5-hydroxy-6S -methyl-27/ -pyran-2R -yl)tetrahy dress -methyl-2S -furanyl] -4S -hydroxy-37 ,5S -dimethyl-6-oxononyl]-2-hydroxy-3-methylbenzoic acid 

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Polyethers. Antibiotics within this family contain a number of cycHc ether and ketal units and have a carboxyHc acid group. They form complexes with mono- and divalent cations that ate soluble ia aoapolar organic solvents. They iateract with bacterial cell membranes and allow cations to pass through the membranes causiag cell death. Because of this property they have been classified as ionophores. Monensia, lasalocid, and maduramicia are examples of polyethers that are used commercially as anticoccidial agents ia poultry and as growth promotants ia mmiaants. 

Table 1 Hsts the polyether antibiotics arranged by the number of carbons in the skeleton. Many of these compounds were isolated independendy in separate laboratories and thus have more than one designation. The groups are subdivided depending on the number of spiroketals. Two classes fall outside this scheme the pyrrole ether type containing a heterocycHc ring, and the acyltetronic acid type, that has an acyHdene tetronic acid instead of a carboxyHc acid. These compounds are ionophores and because of their common features are included as polyethers.

Westley, J. W., ed., Polyether Antibiotics Naturally Occuring Ionophores, Vols. 1 and 2. Dekker, New York, 1982. 

The ion selectivities displayed by these antibiotics are lower than those of the neutral ionophores, and are given in Table 11. Many studies have been made on the properties of these ionophores, particularly with reference to the calcium-transporting abilities of A 23187 (146) and lasolocid (145). The search for new antibiotics is ongoing and there is constant addition to a list of about 50 distinct polyether antibiotics which have been isolated from various streptomycetes. Representative structures will be discussed here to illustrate the nature of complexation with alkali and alkaline earth metal cations. 

The advent of the polyether antibiotics with the challenging aspect of stereocontrolled construction of the substituted tetrahydrofuran units has greatly extended the chemistry of this oxygen heterocycle. The nonactins (194), lasalocid A (195) and monensin (196) are among the ionophores for which syntheses have been achieved. Detailed reviews on synthesis of reduced furans are available (65HOU(6/3)l, 80H(14)1825). 

Because the stability constant of its complex with potassium is much greater than that with sodium, valinomycin is a relatively specific potassium ionophore. In contrast, the mushroom peptide antamanide has a binding cavity of a different geometry and shows a strong preference for sodium ions.388,390 The structure of the Na+-antamanide complex is also shown in Fig. 8-22B. The Streptomyces polyether antibiotic monensin (Fig. 8-22D),389,391 a popular additive to animal feeds, is also an ionophore. However, its mode of action, which involves disruption of Golgi functions, is uncertain 392... 

Ionophores -as animal growth regulators [GROWTH REGULATIONS - ANIMAL] (Vol 12) -polyether antibiotics as [ANTIBIOTICS - POLYETHERS] (Vol 3) -rolem sodium pump POTASSIUM COMPOUNDS] (Vol 19)... 

Particular attention should be paid to ionophore A23187, a polyether antibiotic produced by Streptomyces organisms, which also synthesize a range of other polyether antibiotics. This ionophore has been used extensively in the mediation of calcium transport in a diverse range of processes. The structure of A23187 is included in Figure 5. Its absolute configuration is known.1 3... 

The masked tetrahydroxyketone 28 (Fig. 7) which can theoretically give isomers 29 and 30, was found to yield isomer 29 exclusively (26). The structure of 29 was proven by X-ray analysis. Similarly, dibromodihydroxyketone 31 can give either isomer 32 or 33. Upon cyclization, isomer 32 was the product formed (27) and its structure was also established by X-ray (28). The recently reported total synthesis of ionophore A-23187 (29), a polyether antibiotic whih possesses the 1,7-dioxaspiro[5.5]undecane skeleton having a conformation equivalent to 29 and 32 confirms these results. 

Polyether antibiotics contain tetrahydrofuran rings. In monensin 11, three tetrahydrofuran rings are linearly connected. The molecule contains 17 asymmetric centres. Stereoselective syntheses for monensin have been elaborated [18]. In nonactin 12, the rings are interconnected in an a,a -orientation via ester groupings. Nonactin is therefore classed as a macrolide antibiotic. Polyethers of the type 11/12 are capable of facilitating ion transport across biological membranes they are, therefore, also known as ionophores. 

Polyether lonophores. Isolation and identification of antibiotic X-14885A was reported.Its structure is closely related to A-23187 and cezomycin, members of the pyrrolether class of natural ionophores. Aspects of the discovery and ionophoric properties of the X-14868 complex were described. Another new naturally derived agent, CP-53607 (32), was reported to be effective t ainst coccidia and as a rumen propionic acid stimulant. The C-26 urethane analogs of monensin transported both Rb and Ca. Their antibacterial and anticoccidial activities were also reported as greater than monensin. Microbial conversion of grisorixin by Streptomyces rimosus was found to produce an inactive and detoxified product. A unified stereochemical model of polyether antibiotic structure and biogenesis was proposed. Ibtal synthesis of ionophores continued to be of interest and the unnatural enantiomer of lasalocid A was found to have similar biolc cal properties to the natural product. ... 

J. W. Westley, Polyether Antibiotics Naturally occurring acid ionophors, Vol. I II, Marcel Dekker, Inc. New York (1982). 

Salinomycin, Na salt [5. albus] 772.99 ethanol, DMF polyether antibiotic exhibiting a rare tricyclic spiroketal ring system K -specific ionophore... 

A mixture of ionophoric polyether antibiotics produced by Streptomyces lasaliensis, from which the components A to E have been separated. L. exert antibacterial and antiviral (HIV) activities, LD50 (mouse p.o.) 146 mg/kg. L. A mp. 110-114°C, (aJo -7.5° (CH3OH), which preferentially forms complexes with divalent cations, is formed biosynthetically by the polyketide pathway from five acetate units, four propionate units, and three butanoate units, the benzene ring arises through cyclization. L. A (Bovatec ) in the form of its sodium salt (Avatec ) is used in fowl breeding as a coccidostatic. 

C42H70O11, Mr 751.01, cryst., mp. 112.5-113.5 °C, [a]o -63 (C2H5OH), an ionophoric polyether antibiotic with a dispiroketal structure produced by Strep-tomyces albus it preferentially forms complexes with monovalent cations (Na ). S. is formed biosyntheti-cally on the polyketide pathway, cyclization in the linear carboxylic acid proceeds on the diene/diepox-ide pathway. The 20-deoxy derivative is also formed. S. is used against coccidiosis in poultry breeding and also has antiviral activity (HIV). LD50 (mouse p.o.) 50 mg/kg. 

Tetronomycin (TMN), a polycyclic ionophoric polyether antibiotic, was isolated in 1982 from a strain of Streptomyces sp (Figure 5.67) [267]. TMNs structure and absolute configuration were established on the basis of extensive NMR studies and X-ray analysis of the mono-O-acetyltetronomycin silver salt, which showed it to be 68. 

Generally, two different modes of transmembraneous transport have been established the carrier and the channel mechanism. The ionophores considered here act by the carrier mechanism. They form discrete antibiotic cation complexes at one interface of the membrane which then migrate across the membrane to the other interface where the metal ion is released. This kind of transport is displayed by the depsipeptide-type antibiotics which form positively charged complexes with metal ions. This is also true for the macrotetrolide nactins whereas the open-chain polyether antibiotics of the nigericin family mainly lead to electrically neutral metal ion complexes by dissociation of their carboxyl group. For the latter type of carriers, the ion transport of metal ions is coupled with a transfer of protons in the opposite direction. 

The ionophores we shall discuss in this section are referred to as nigericin antibiotics because nigericin was the first compound of this family to be discovered Other common designations are carboxylic acid ionophores and polyether antibiotics, describing essential structural features of these biomolecules which are unique among the ionophores described so far because they are linear and contain... 

The lasalocids have several unique features such as a salicyclic acid moiety and a carbonyl group. Furthermore, their ligand backbones are considerably shorter than those of the other polyether antibiotics (see Fig. 15). This accounts for the inability of lasalocid ionophores to fully shield the complexed metal ion from the solvent by folding around it. The resulting complex has two distinct surfaces one of which is much more polar than the other, as demonstrated in Fig. 18 for lasalocid A, the most abundant species. In non-polar media, this unfavorable situation is overcome by the formation of dimeric complexes of stoichiometries (M L") and M (L")j for mono- and divalent metal ions, respectively. In fact, these aggregates present a highly lipophilic surface to the solvent. 

Table 7b. Divalent polyether antibiotics Bonding distances in their complexes with metal ions. In the case of 2 1 complexes, the ionophore molecules are referred to as A and B ...

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