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1.D.15 The Daptomycin (Daptomycin) Family

Daptomycin, DAP, a cyclic lipopeptide produced by Streptomyces roseosporus, is the active ingredient of Cubicin (daptomycin-for-injection), a first-in-class antibiotic approved for treatment of skin and skin-structure infections caused by Gram-positive pathogens and bacteremia and endocarditis caused by Staphylococcus aureus, including methicillin-resistant strains (Hawkey, 2008; Nguyen et al., 2006). It has a novel mechanism of action: disruption of the functional but not structural integrity of the Gram positive plasma membrane (PM). Daptomycin undergoes calcium-dependent membrane insertion forming pores, resulting in leakage of intracellular ions, including potassium, and a loss of membrane potential (van Bronswijk, 2007). It oligomerizes in the membrane to form the pore (Muraih et al., 2011). 

Daptomycin treatment alters the regulation of cell division, but not its underlying biochemistry. Septal placement in bacteria is negatively regulated, and new synthesis is blocked at all sites except the midline. Daptomycin treatment may displace the factors that normally block inappropriate synthesis. Disruption of cell division may be a result of ion leakage and depolarization. Alternatively, the insertion of daptomycin into the cytoplasmic membrane may impair cross-talk between the membrane and the cell wall. (Cotroneo et al., 2004).

Daptomycin and related acidic cyclic lipopeptide antibiotics have ten amino acids in the ring, and exocyclic tails containing one or three amino acids. The N-termini of the exocyclic amino acids are generally coupled to long chain fatty acids (Baltz, 2008). Biosynthesis is initiated by the coupling of fatty acids to the N-terminal amino acids, followed by the coupling of the remaining amino acids by nonribosomal peptide synthetase (NRPS) mechanisms, then cyclization and release of the lipopeptides. The biosynthetic genes for daptomycin, calcium dependent antibiotic (CDA), A54145 and friulimicin have been cloned, sequenced, analyzed bioinformatically, and in some cases, studied genetically or biochemically. The information on the organization and expression of the NRPS and other genes has been exploited to generate combinatorial libraries of hybrid lipopeptide antibiotics related to daptomycin, including several compunds with very good antibacterial activities (Baltz, 2008).

The reaction catalyzed by Daptomycin is:

small molecules (in) ⇌ smail molecules (out)

 

References associated with 1.D.15 family:

Baltz, R.H. (2008). Biosynthesis and genetic engineering of lipopeptide antibiotics related to daptomycin. Curr Top Med Chem 8: 618-638. 18473888
Cotroneo, N., B. Harris, T. Beveridge, and J.A. Silverman. (2004). Further Studies of Daptomycin-Induced Membrane and Cell-Wall Alterations in Staphylococcus aureus, Enterococcus faecalis, and Bacillus subtilis. Poster# C1-951.
Hawkey, P.M. (2008). Pre-clinical experience with daptomycin. J Antimicrob Chemother 62Suppl3: iii7-14. 18829726
Muraih, J.K., A. Pearson, J. Silverman, and M. Palmer. (2011). Oligomerization of daptomycin on membranes. Biochim. Biophys. Acta. 1808: 1154-1160. 21223947
Nguyen, K.T., D. Ritz, J.Q. Gu, D. Alexander, M. Chu, V. Miao, P. Brian, and R.H. Baltz. (2006). Combinatorial biosynthesis of novel antibiotics related to daptomycin. Proc. Natl. Acad. Sci. USA 103: 17462-17467. 17090667
van Bronswijk, H., E.A. Dubois, J.T. van Dissel, and A.F. Cohen. (2007). [New drugs; daptomycin]. Ned Tijdschr Geneeskd 151: 2777-2778. 18232197