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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). Membrane permeabilization requires both calcium and phosphatidylglycerol (PG) in the target membrane. The protein oligomerizes in the membrane to form the pore with 4 subunits in the outer leaflet and 4 in the inner leaflet (Muraih et al., 2011). The octamer is probably the functional transmembrane pore, and fatty acyl residues may prevent pore formation by preventing the alignment of tetramers across the two membrane leaflets (Beriashvili et al. 2018).

Daptomycin's bactericidal action involves calcium-dependent binding to membranes containing phosphatidylglycerol, followed by the formation of membrane-associated oligomers. Bacteria exposed to daptomycin undergo membrane depolarization, suggesting the formation of pores. Zhang et al. 2014 used a liposome model to detect and characterize the permeability properties of the daptomycin pores. Permeabilities were highest for Na+, K+, and other alkali metal ions. Permeability was approximately two-fold lower for Mg++, and lower still for organic cations such as choline and hexamethonium. Anions were excluded, as was the zwitterion cysteine. Under typical in vivo conditions, depolarization is probably due to sodium influx.

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) ⇌ small 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
Beriashvili, D., R. Taylor, B. Kralt, N. Abu Mazen, S.D. Taylor, and M. Palmer. (2018). Mechanistic studies on the effect of membrane lipid acyl chain composition on daptomycin pore formation. Chem Phys Lipids 216: 73-79. 30278162
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
Zhang, T., J.K. Muraih, B. MacCormick, J. Silverman, and M. Palmer. (2014). Daptomycin forms cation- and size-selective pores in model membranes. Biochim. Biophys. Acta. 1838: 2425-2430. 24857935