Daptomycin structure

One interesting outcome of sequencing the daptomycin gene cluster was the prediction of the stereochemical structure. The original structure proposed by 

The location (in base pairs) of the giant dptA, dptBC and dptD genes cloned on BAC pVCl which contains a 128 000 base pair insert.14 The dptA, dptBC and dptD genes encode five, six and two modules, respectively. The specificity of A domains is shown with amino acid subscripts. The C condensation domain differs from the others in that it couples the long chain fatty acids to the TV-terminus of Trp i to initiate daptomycin biosynthesis. Note that modules 2, 8 and 11 have CATE modules to incorporate D-amino acids. The Kyn13 module has a terminal Te (as CATTe) to cyclise and release the completed lipopeptide. 

The Cubist DNA sequencing work is an example of the powerful predictive nature of the DNA sequences encoding secondary metabolites, which should be useful in the discovery of novel antibiotics from fully sequenced actinomycete 

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Figure 11.5 Amino acid building blocks are incorporated into daptomycin backbone successively by NRPS subunits DptA, DptBC and DptD (a). Structural diversity of daptomycin peptide core can be obtained by genetic modifications of dpt gene cluster (b). C, condensation domain A, adenylation domain PCP, peptidyl carrier protein E, epimerase TE, thioesterase domain... 

Gu, J.Q., Nguyen, K.T., Gandhi, C. et al. (2007) Structural characterization of daptomycin analogues A21978C1 3(D-Asn11) produced by a recombinant Streptomyces roseosporus strain. Journal of Natural Products, 70, 233. 

Kopp, F., Grunewald, J., Mahlert, C. and Marahiel, M.A. (2006) Chemoenzymatic design of acidic lipopeptide hybrids new insights into the structure-activity relationship of daptomycin and A54145FNR Biochemistry, 45, 10474. 

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... 

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. 

Jung D, Rozek A, Okon M, Hancock RE. (2004) Structural transitions as determinants of the action of the calcium-dependent antibiotic daptomycin. Chem Biol 11 949-957. 

Compounds that disrupt cell membrane integrity either through structural or functional disorganization lead to loss of viability. Polymyxins and daptomycin (Fig. 5) are examples of cell membrane inhibitors. 

Complicated skin and skin structure infections Administer daptomycin 4 mg/kg over a 30-minute period by IV infusion in 0.9% sodium chloride injection once every 24... 

Daptomycin is an important antibiotic approved for the treatment of complicated skin and skin structure infections caused by Gram-positive pathogens1 and for treatment of bacteraemia, including right-sided endocarditis caused by Staphylococcus aureus strains, including those resistant to methicillin (MRSA).2... 

Figure 14.1 Structures of A21978C factors and daptomycin (Reprinted with permission from Baltz et al.3).

Figure 2 A selection of nonribosomal peptides. Chemical and structural features that contribute to the vast diversity of this class of metabolites are highlighted Heterocycle (bacitracin), lactone (surfactin, daptomycin), ornithine and lactam (Tyrocidine), sugar, chlorinated aromats, C-C crosslink (Vancomycin), N-formyl groups (Coelichelin and linear gramicidin), fatty acid (daptomycin), dihydroxybenzoate and trimeric organization (bacillibactin), dimeric organization (gramicidin S), and ethanolamine (linear gramicidin).

Fig. 10. Structure of daptomycin where L-Kyn is L-kynurenine and (L-threo) 3-MeGlu is L-/ m 3-methylglutamic acid...

Daptomycin is a lipopeptide that binds to bacterial membranes and canses a rapid depolarization of membrane potential, which inhibits protein, DNA, and RNA synthesis, resulting in bacterial cell death. Daptomycin is indicated in treatment of complicated skin and skin structure infections caused by susceptible strains of Gram-positive microorganisms. 

Daptomycin is indicated for treatment of complicated skin and skin-structure infections caused by methicillin-susceptible and methicillin-resistant strains ofS. aureus, hemolytic streptococci, and vancomycin-susceptible E. faecalis. Its efficacy is comparable to that of 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. 

An enormous range of medically important polyketide and peptide natural products assembled by modular polyketide synthases (PKSs), non-ribosomal peptide synthases (NRPSs) and mixed PKS/NRPS systems have macrocyclic structures, including the antibiotics erythromycin (PKS) and daptomycin (NRPS), the immunosuppressants cyclosporin (NRPS) and rapamycin (PKS/NRPS), and the antitumor agent epothilone (PKS/NRPS). PKSs and NRPSs are large, multifunctional proteins that are organized into sets of fnnc-tional domains termed modules. The order of modules corresponds directly to the seqnence of monomers in the product. Synthetic intermediates are covalently tethered by thioester linkages to a carrier protein domain in each module. The thiol tether on each carrier domain is phosphopantetheine, which is attached to a conserved serine residne in the carrier protein in a post-translational priming reaction catalyzed by a phosphopantetheinyltransferase. 

Fig. 3.38 Two natural antibiotics the relatively simple benzylpenicillin, and daptomycin, which is complex both in its chemical structure and physiological effects. (Authors own work)...

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