Cyclic lipopeptide structures

Even newer is the natural product daptomycin (Cubicin), a complex cyclic lipopeptide structure, approved for use in the United States in 2003. Daptomycin has a spectrum similar to that of linezolid and specifically includes MRSA and VRE. In contrast to linezolid, daptomycin is bactericidal for these Gram-positive organisms. It is, like vancomycin, a parenteral antibiotic and is given intravenously. It is indicated for treatment of complicated skin and skin structure infections and for some cases of bacteremia, including endocarditis. Daptomycin may be thought of as an alternative to vancomycin. 

Daptomycin is a fermentation product having a cyclic lipopeptide structure. It is primarily active against Gram-positive infections, especially those involved in skin/skin structure infections. It is given IV but must be administered over a period of 30 minutes or more. It binds to cell membranes and causes depolarization, which interrupts protein, DNA, and RNA synthesis. Daptomycin is bactericidal. Although resistance can be achieved in vitro, resistance has been slow to emerge in the clinic. Patients should be monitored for muscle pain or weakness, because some incidence of elevated serum creatinine phosphokinase is associated with its use. A small number of clinical trial patients also developed conditions related to decreases in nerve conduction (e.g., paresthesias and Bell s palsy). Daptomycin is eliminated primarily by the kidney, so dose adjustment may be necessary in cases of renal insufficiency. 

B. anthracis and related species.41,44 6 Some of these peaks have been identified (e.g., as small acid soluble spore proteins and cyclic lipopeptides), but others remain uncharacterized. There is no agreement among different laboratories as to which markers are suitable for chemotaxonomic differentiata-tion of species (i.e., are consistently found in one species versus another) or for strain identification (i.e., are reproducibly found in one strain but not another). Further, although it might be anticipated that surface proteins can be preferentially ionized or extracted, the ultra-structural origin of some peptides within the cell is not always clear. 

Bonnard, I., Rolland, M., Francisco, C, and Banaigs, B. (1997). Total structure and biological properties of laxaphycins A and B, cyclic lipopeptides from the marine cyanobacterium Lyngbya majuscula. Lett. Pept. Sci. 4, 289-292. 

Cyclic lipopeptide antibiotics can be classified structurally into several groups. The enormous structural diversity in this group of antibiotics leads... 

Leucine-rich cyclic lipopeptides are mainly produced by gram-positive Bacillus spp. and gram-negative Pseudomonas fluorescens. Their structural similarity is not always reflected in their biological activity, and they exhibit some diversity in this regard. 

A lot of interesting lipopeptides, both terms of biological activities and structures, have been discovered from the metabolites of marine-associated organisms. In particular, cyanobacteria produce many kinds of bioactive metabolites including toxins and enzyme inhibitors. Some cyclic lipopeptides from marine-associated organisms have unique structures, which are much different from those of their soil-associated counterparts. For example, the a-diketo structure is in cyclotheonamides 3-amino-6-hydroxy-2-piperidone is in micropeptins, scyptolins and planktopeptins and (2S, 3S, 8S,... 

Cyclic lipopeptide antibiotics contain various kinds of amino acids including unusual amino acids. Many kinds of cyclic lipopeptides were discovered from microorganisms and they often exhibit a wide variety of biological activities such as antimicrobial, antifungal, antitumor, and enzyme inhibitory activities. It is also of considerable interest that the structural similarities do not always reflect any similarity of biological activities in the cyclic lipopeptides. 

The structural and biological diversity of the cyclic lipopeptide antibiotics is extremely attractive to chemical, pharmacological and medical sciences. Future rational drug design, chemical modification and discovery of novel cyclic lipopeptides from natural sources will give rise to useful biological tools for research and development in the medicinal sciences. 

R 345 M. Blaut, L. Schoefer and A. Braune, Transformation of Flavonoids by Intestinal Microorganisms , Int. J. Vitam. Nutr. Res., 2003,73,79 R 346 J. -M. Bonmatin, O. Laprevote and F. Peypoux, Diversity among Microbial Cyclic Lipopeptides Iturins and Surfactins. Activity - Structure Relationships to Design New Bioactive Agents , Comb. Chem. High T. Scr., 2003,6, 541... 

Surfactin is a cyclic lipopeptide produced by B. subtilis.The chemical structure consists of several variants differing in their fatty acid chain and their peptide moiety.They comprise a peptide loop of seven amino acids (t-asparagine, L-leucine, glutamic acid, L-leucine, L-valine and two D-leucines), and a a, -hydroxy C13-C15 fatty acid chain (Figure 14.7). 

Polymyxins are cyclic lipopeptides with a general structure consisting of a cyclic peptide with a long hydrophobic tail produced by Paenibacillus species. Different structural variants of polymyxin are produced by different species of Paenibacillus genera. Polymyxin B is produced by Paenibacillus polymyxa, while Polymyxin E (also known as colistin) is produced by Ppolymyxa and Paenibacillus amylolytkus (Figure 14.10). ... 

Lichenysin are cyclic lipopeptides produced by Bacillus licheniformis. The structure of lichenysin varies with the species, which make them categorized into A, B, C, D, and G. Lichenysin is structurally similar to surfactin, whereas surfactin has a cyclic peptide of seven amino acids including both d- and L-amino acids, Glu-Leu-D-Leu-Val-Asp-D-Leu-Leu, linked from the N-terminus to the C-terminus to form a cyclic moiety by a C12-C17 P-hydroxy fatty acid, Hchenysin has a structure with the primary amino acid sequence L-Gln-L-Leu-D-Leu-L-Val-L-Asp-D-Leu-L-Ile, with minor Leu and Val substitutions at the seventh position (Figure 14.12). 

Yokokawa, F. and Shioiri, T. (1998) Total synthesis of antillatoxin, an ichthyotoxic cyclic lipopeptide, having the proposed structure. What is the real structure antillatoxin J, Org. Chem., 63, 8638-8639. 

One of the most characteristic features of FRET is its sensitive dependency on the fluorophore distance. This is advantageously used to evaluate structures and conformational changes of peptides, glycopeptides, and proteins among other molecules [164-166], The conformational change of the lipopeptide antibiotic daptomycin from an inactive linear form to a biological active cyclic form... 

The cyanotoxins display remarkable structural diversity, however, most can be classified as cyclic peptides, depsipeptides, lipopeptides, or alkaloids [15-17]. Among the alkaloid neurotoxins, which are the focus of this chapter, anatoxin-a and homoanatoxin-a can be described as low molecular weight secondary bicyclic... 

The polymyxins are a group of closely related lipopeptide antibiotics produced by B. polymyxa and related bacilli. As seen in O Fig. 10.5, polymyxin B is a decapeptide in which amino acids 3 through 10 form a cyclic octapeptide. A branched-chain fatty acid is connected to the terminal 2,4-diaminobutyric acid (DAB). The structures of polymyxins differ in substituents at residues 3 (DAB or D-Ser), 6 (o-Leu or L-Ileu), or 7 (d- or l-DAB) (Suzuki et al. 1965). The cationic 7y-amino groups of the DAB residues, together with the hydrophobic side chain of the fatty acid, give these antibiotics the surface-active properties of a cationic detergent. Pseudomonas strains produce viscosin, a peptidolipid biosurfactant which lowers surface tension of water to 27 mN/m (Neu et al. 1992). 

The two well-studied lipopeptide bioemulsifiers produced by Bacilli—surfactin (Peypoux et al. 1999) and lichenysin (Yakimov et al. 1995)—are structurally similar. As already mentioned, both are composed of a cyclic heptapeptide linked to a fatty acid and differ in the last amino acid of the peptide—leucine and isoleucine, respectively. The peptide moiety, like many small peptides in microorganisms, is synthesized non-ribosomally by a multienzyme peptide synthetase complex (Marahiel 1997). The srfA operon of B. subtilis was defined by a transposon... 

In the course of screening for inhibitors of cyclic adenosine-3, 5 -monophosphate phosphodiesterase, a strain of B. subtilis was found to produce a series of such inhibitors. These compounds with a m.p. of 136-139 °C and an optical rotation of -h 37° to 38.5° (chloroform), — 33° to — 38° (methanol), were lipopeptides with the same peptide moiety as surfactin. Their fatty acid components were 3-hydroxy-ll-methyldodecanoic acid, 3-hydroxy-10-methyldodecanoic add, 3-hydroxytetradecanoic acid (the major component), 3-hydroxy-13-methyltetradecanoic acid (the same acid as that of surfactin) and 3-hydroxy-12-methyltetradecanoic acid (707, 702). The location of the lactone ring was established by the same method as that used for surfactin 96), Therefore these inhibitors had structures quite similar to, and for one of them identical with, that of surfactin (40). 

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