Divalent Polyether Antibiotics

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. 

An arrangement of this type was first shown by X-ray crystallography to exist in the barium complex of lasalocid In this complex, two antibiotic anions 

Discrete dimers of the head-to-tail type have also been found in the crystal structures of the 2 2 lasalocid complexes with Ag and Na when 

However, when the sodium complex was crystallized from a solvent of medium polarity such as acetone, a head-to-head dimer structure was obtained This is also true for the free acid of 5-bromolasalocid crystallized from CgHj /CH Clj in which the antibiotic molecules are connected to each other by a hydrogen-bonded water molecule and by an additional hydrogen bond from the carboxy group of one ligand to the carbonyl group of the other. 

The dimeric structures found in the crystalline state have also been detected in non-polar solutions by NMR spectroscopy but the spectral data obtained in polar solvents where not consistent with such adducts Instead, they suggested the presence of simple 1 1 complexes. To assess the influence of solvent polarity, Paul and coworkers examined the crystal structures of free lasalocid and of its sodium complex crystallured from methanol, and, indeed, found these to be monomers i39) Both structures display the familiar head-to-tail hydrogen bonding. In the sodium complex, the Na is coordinated to the same five ligand oxygens as in the dimeric structure, but it is capped by the oxygen of a methanol molecule. 

---

The divalent polyether antibiotics have revealed the existence of dimeric molecules as monomeric complexes in their interaction with alkali and alkaline earth cations. Lasolocid (145) forms complexes of the type M+L and these may be monomeric when formed and recovered from methanol, but dimeric when recrystallized from the non-polar carbon tetrachloride. The shortened ligand backbone relative to the monovalent polyethers does not allow complete shielding of the cation from the solvent, and so in non-polar solvents this is overcome by dimerization. If the salicylate and tetrahydropyran moieties present in (145) are referred to as the head and the tail of the molecule then two forms of dimerization may be envisaged head-to-tail and head-to-head . 

The divalent polyether antibiotics are much fewer in number than those of the first group. The most popular representatives are lasalocid, formerly known as antibiotic X-537A, and A23187. More recently discovered examples are lysocellin ionomycin and antibiotic X-14547 A (see Fig. 15). Actually, the... 

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 ...

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. 

Lasalocid is the more disruptive polyether antibiotic to biological systems. This is due to its high tendency to dimerize and form complexes with biologically important divalent ions such as ("a and Mg ". Lasalocid exhibits a wide range of complexation affinities and transport capabilities, encompassing not only inorganic polyvalent ions but also primary amines and catecholamines (22). 

S. malachitofuscus produces X14766A, the only chlorine containing polyether antibiotic (39) described so far. The producer was isolated from the Mexican soil in 1976. The antibiotic is active against Gram-positive bacteria forming strong complexes with both monovalent and divalent metals (K, Na, Rb, Cs, Ba, Sr, Ca, Mg, Li) [27,28]. 

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. 

F. 15. Divalent polyether and pyrrole ether antibiotics mentioned in the text... 

Ionophores, or polyether (PET) antibiotics, produced by various species of Streptomyces, possess broad spectrum anticoccidial activities. They are chemically characterized by several cyclic esters, a single terminal carboxylic acid group, and several hydroxyl groups. Representative members of this class include salinomycin (SAL), monensin (MON), lasalocid (LAS), narasin (NAR), maduramicin (MAD), and semduramicin (SEM). The main chemical properties of interest in the extraction methodology are their low polarities and instability under acidic conditions. They are able to form stable complexes with alkaline cations. All of these compounds, with the exception of LAS, bind monovalent cations (e.g., Na+ and K+). Lasalocid has a tendency to form dimers and can form complexes with divalent cations such as Mg2+ and Ca2+. The formation of metal complexes results in all of these compounds adopting a quasi-cyclic formation consequent to head-to-tail hydrogen bonding. No MRLs have yet been set by the EU for any of the carboxylic acid PETs (98). 

---