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This is a work in progress for the daptomycin page. Any feedback would be appreciated. --K. Beabout (talk) 15:58, 4 June 2013 (UTC)

KatieBNL/sandbox
Daptomycin Ball et al.svg
Systematic (IUPAC) name
N-decanoyl-L-tryptophyl-L-asparaginyl-L-aspartyl-L-threonylglycyl-
L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo -3-methyl-L-glutamyl-3-anthraniloyl-L-alanine[egr]1-lactone
Clinical data
Trade names Cubicin
AHFS/Drugs.com monograph
Pregnancy cat. B (US)
Legal status -only (US)
Routes Intravenous
Pharmacokinetic data
Bioavailability n/a
Protein binding 90–95%
Metabolism Renal (speculative)[1]
Half-life 7–11 hours (up to 28 hours in renal impairment)
Excretion Renal (78%; primarily as unchanged drug); Faeces (5.7%)
Identifiers
CAS number 103060-53-3 YesY
ATC code J01XX09
PubChem CID 16129629
DrugBank DB00080
ChemSpider 10482098 YesY
UNII NWQ5N31VKK YesY
KEGG D01080 N
ChEMBL CHEMBL508162 N
Chemical data
Formula C72H101N17O26 
Mol. mass 1619.7086 g/mol
 N (what is this?)  (verify)
Identifiers
TCDB 1.D.15
OPM superfamily 172
OPM protein 1t5n

Daptomycin is a lipopeptide antibiotic used in the treatment of systemic and life-threatening infections caused by Gram-positive organisms. It is a naturally occurring compound found in the soil saprotroph Streptomyces roseosporus. Its distinct mechanism of action makes it useful in treating infections caused by multi-resistant bacteria. It is marketed in the United States under the trade name Cubicin by Cubist Pharmaceuticals.

History[edit]

The compound LY 146032 was discovered by researchers at Eli Lilly and Company in the late 1980s.LY 146032 showed promise in Phase I/II clinical trials for treatment of infection caused by Gram-positive organisms. Lilly ceased development because high-dose therapy was associated with adverse effects on skeletal muscle, including myalgia and potential myositis.

The rights to LY 146032 were acquired by Cubist Pharmaceuticals in 1997, which following U.S. Food and Drug Administration (FDA) approval in September 2003 for use in people older than 18 years began marketing the drug under the trade name CUBICIN. Cubicin is marketed in the EU and in several other countries by Novartis following its purchase of Chiron Corporation, previous licensee.[2][3]

Mechanism of action[edit]

Daptomycin has a distinct mechanism of action, disrupting multiple aspects of bacterial cell membrane function. It inserts into the cell membrane in a phosphatidylglycerol dependent fashion, where it then aggregates. The aggregation of daptomycin alters the curvature of the membrane, which creates holes that leak ions. This causes rapid depolarization, resulting in a loss of membrane potential leading to inhibition of protein, DNA and RNA synthesis, which results in bacterial cell death.[4]

Microbiology[edit]

Daptomycin is bactericidal against Gram-positive bacteria only. It has proven in vitro activity against enterococci (including glycopeptide-resistant Enterococci (GRE)), staphylococci (including methicillin-resistant Staphylococcus aureus), streptococci and corynebacteria.

Daptomycin resistance[edit]

Daptomycin resistance is still uncommon but has been increasingly reported in GRE, starting in Korea in 2005, in Europe in 2010, in Taiwan 2011, and in the USA, where 9 cases have been reported from 2007 to 2011.[5] Daptomycin resistance emerged in 5 of the 6 cases, while they were treated. The mechanism of resistance is unknown.

Clinical use[edit]

Indications[edit]

Daptomycin is approved for use in adults in the United States for skin and skin structure infections caused by Gram-positive infections, Staphylococcus aureus bacteraemia and right-sided S. aureus endocarditis. It binds avidly to pulmonary surfactant, and therefore cannot be used in the treatment of pneumonia.[6] There seems to be a difference in working daptomycin on hematogenous pneumonia.[7]

Efficacy[edit]

Daptomycin has been shown to be not inferior to standard therapies (nafcillin, oxacillin, flucloxacillin or vancomycin) in the treatment of bacteraemia and right-sided endocarditis caused by Staphylococcus aureus.[8] A study in Detroit, Michigan compared 53 patients treated suspected MRSA skin or soft tissue infection with daptomycin against vancomycin, has been shown to result in faster recovery from skin and soft tissue infections (4 days versus 7 days).[9] The main problems with this study were that vancomycin controls were historical (which means that the improved outcomes observed in the daptomycin treated patients could be due to improvements in practice over time that were unrelated to daptomycin use), and the target drug levels were low (lower limit 5 mg/dl, compared to the 10 mg/dl or 15 mg/dl currently recommended).

In Phase III clinical trials, limited data showed that daptomycin was associated with poor outcomes in patients with left-sided endocarditis[citation needed]. It is inactivated by pulmonary surfactants and is not indicated for the treatment of pneumonia. Daptomycin has not been studied in patients with prosthetic valve endocarditis or meningitis.[10]

Dosage and presentation[edit]

In skin and soft tissue infections, 4 mg/kg daptomycin is given intravenously once daily. For S. aureus bacteraemia or right-sided endocarditis, the approved dose is 6 mg/kg given intravenously once daily.

Daptomycin is given every 48 hours in patients with renal impairment, clearance < 30 ml/min. There is no information available on dosing in people less than 18 years of age.

Daptomycin is supplied as a sterile preservative-free pale yellow to light brown lyophilised 500 mg and 350 mg cake that must be reconstituted with 0.9% saline prior to use.

Daptomycin is applicable as 30-min-infusion or 2-min-injection.

Adverse effects[edit]

Adverse drug reactions associated with daptomycin therapy include:[11]

There are also reports of myopathy and rhabdomyolysis occurring in patients simultaneously taking statins[12] but whether this is due entirely to the statin or whether daptomycin potentiates this effect is unknown. Due to the limited data available, the manufacturer recommends that statins be temporarily discontinued while the patient is receiving daptomycin therapy.

In July 2010, the FDA issued a warning that Daptomycin could cause life-threatening eosinophilic pneumonia. The FDA said that it had identified seven confirmed cases of eosinophilic pneumonia between 2004 and 2010 and an additional 36 possible cases. The seven confirmed victims were all older than 60 and symptoms appeared within two weeks of initiation of therapy.

Biosynthesis[edit]

Figures 1-7. Biosynthesis of Daptomycin
Figure 8. Structures of lipopeptide antibiotics. Colors highlight the positions in daptomycin that have been modified by genetic engineering, as well as the origins of modules or subunits from A54145 or calcium-dependent antibiotic (CDA).[13]
Figure 9. Combinatorial biosynthesis of lipopeptide antibiotics related to daptomycin. Position 8, which typically has D-Ala in daptomycin, was modified by module exchanges to contain D-Ser, D-Asn or D-Lys; position 11, which naturally has D-Ser, was modified by module exchanges to consist of D-Ala or D-Asn; position 12, which normally has 3-methyl-L-Glu, was modified by deletion of the methyltransferase gene to possess L-Glu; position 13, which normally has L-kynurenine (L-Kyn), was modified by subunit exchanges to contain L-Trp, L-Ile or L-Val; position 1 usually includes the anteiso-undecanoyl, isododecanoyl and anteiso-tridecanoyl fatty acyl groups. All of these alterations have been combinatorialized. [13]

Daptomycin is a cyclic lipopeptide antibiotic produced by the organism Streptomyces roseosporus.[14][15] Daptomycin consists of thirteen amino acids, ten of which are arranged in a cyclic fashion, and three that adorn an exocyclic tail. Two non-proteinogenic amino acids exist in the lipopeptide, the unusual amino acid L-kynurenine (Kyn), only known to Daptomycin, and L-3-methylglutamic acid (mGlu). The N-terminus of the exocyclic tryptophan residue is coupled to decanoic acid, a medium chain (C10) fatty acid. Biosynthesis is initiated by the coupling of decanoic acid to the N-terminal tryptophan, followed by the coupling of the remaining amino acids by nonribosomal peptide synthetase (NRPS) mechanisms. Finally, a cyclization event occurs, which is catalyzed by a thioesterase enzyme, and subsequent release of the lipopeptide is granted.

The non-ribosomal peptide synthetase (NRPS) responsible for the synthesis of Daptomycin is encoded by three overlapping genes, dptA, dptBC and dptD. The dptE and dptF genes, immediately upstream of dptA, are likely to be involved in the initiation of daptomycin biosynthesis by coupling decanoic acid to the N-terminal Trp.[16] These novel genes (dptE, dptF ) correspond to products that most likely work in conjunction with a unique condensation domain to acylate the first amino acid (tryptophan). These and other novel genes (dptI, dptJ) are believed to be involved in supplying the non-proteinogenic amino acids L-3-methylglutamic acid and Kyn; they are located next to the NRPS genes.[16]

The decanoic acid portion of Daptomycin is synthesized by fatty acid synthase machinery (Figure 2). Posttranslational modification of the apo-acyl carrier protein (ACP, thiolation, or T domain) by a phosphopantetheinyltransferase (PPTase) enzyme catalyzes the transfer of a flexible phosphopantetheine arm from coenzyme A to a conserved serine in the ACP domain through a phosphodiester linkage. The holo-ACP can now provide a thiol on which the substrate and acyl chains are covalently tethered during chain elongations. The two core catalytic domains are an acyltransferase (AT) and a ketosynthase (KS). The AT acts upon a malonyl CoA substrate and transfers an acyl group to the thiol of the ACP domain. This net transthiolation is an energy neutral step. Next, the acyl-S-ACP gets transthiolated to a conserved cysteine on the KS; the KS decarboxylates the downstream malonyl-S-ACP and forms a β-ketoacyl-S-ACP. This serves as the substrate for the next cycle of elongation. Before the next cycle begins, however, the β-keto group undergoes reduction to the corresponding alcohol catalyzed by a ketoreductase (KR) domain, followed by dehydration to the olefin catalyzed by a dehydratase (DH) domain, and finally reduction to the methylene catalyzed by an enoylreductase (ER) domain. Each KS catalytic cycle results in the net addition of two carbons. After three more iterations of elongation, a thioesterase enzyme catalyzes the hydrolysis, and thus release, of the free C-10 fatty acid.

To synthesize the peptide portion of Daptomycin, the mechanism of a non-ribosomal peptide synthetase (NRPS) is employed. The biosynthetic machinery of an NRPS system is composed of multimodular enzymatic assembly lines that contain one module for each amino acid monomer incorporated.[17] Within each module, there are catalytic domains that carry out the elongation of the growing peptidyl chain. The growing peptide is covalently tethered to a thiolation (T) domain; here it is termed the peptidyl carrier protein (PCP), as it carries the growing peptide from one catalytic domain to the next. Again, the apo-T domain must be primed to the holo-T domain via a PPTase, attaching a flexible phosphopantetheine arm to a conserved serine residue. An adenylation (A) domain selects the amino acid monomer to be incorporated and activates the carboxylate with ATP to make the aminoacyl-AMP. Next, the A domain installs an aminoacyl group on the thiolate of the adjacent T domain (PCP). The condensation (C) domain catalyzes the peptide bond forming reaction, which elicits chain elongation. It joins an upstream peptidyl-S-T to the downstream aminoacyl-S-T (Figure 7). Chain elongation by one aminoacyl residue and chain translocation to the next T domain occurs in concert. The order of these domains is C-A-T. In some instances, an epimerization (E) domain is necessary in those modules where L-amino acid monomers are to be incorporated and epimerized to D-amino acids. The domain organization in such modules is C-A-T-E.[17]

The first module has a three-domain C-A-T organization; these often occur in assembly lines that make N-acylated peptides.[17] The first C domain catalyzes N-acylation of the initiating amino acid (tryptophan) while it is installed on T. An adenylating enzyme (Ad) catalyzes the condensation of decanoic acid and the N-terminal tryptophan, which incorporates decanoic acid into the growing peptide (Figure 3). The genes responsible for this coupling event are dptE and dptF, which are located upstream of dptA, the first gene of the Daptomycin NRPS biosynthetic gene cluster. Once the coupling of decanoic acid to the N-terminal tryptophan residue occurs, the condensation of amino acids begins, catalyzed by the NRPS.

The first five modules of the NRPS are encoded by the dptA gene and catalyze the condensation of L-tryptophan, D-aspartate, L-aspartate, L-threonine, and glycine, respectively (Figure 4). Modules 6-11, which catalyze the condensation of L-ornithine, L-aspartate, D-alanine, L-aspartate, glycine, and D-serine are encoded for the dptBC gene (Figure 5). DptD catalyzes the incorporation of two non-proteinogenic amino acids, L-3-methylglutamic acid (mGlu) and the unusual amino acid L-kynurenine (Kyn), which is only known thus far to Daptomycin, into the growing peptide (Figure 6).[15] Elongation by these NRPS modules ultimately leads to macrocyclization and release in which an α-amino group, namely threonine, acts as an internal nucleophile during cyclization to yield the 10 amino acid ring (Figure 6). The termination module in the NRPS assembly line has a C-A-T-TE organization. The thioesterase (TE) domain catalyzes chain termination and release of the mature lipopeptide.[17]

With the recent advances in molecular engineering over the past 25 years, new approaches in the production of novel antibiotics have emerged. Innovations in cloning and the subsequent analysis of antibiotic gene clusters, the engineering of biosynthetic pathways in Escherichia coli, the transfer of engineered pathways from E. coli into Streptomyces expression hosts, and finally the stable maintenance and expression of cloned genes are all processes that have streamlined the process. More comprehensive understanding and knowledge of the mechanisms, as well as the substrate specificities during their assembly by polyketide synthases, nonribosomal peptide synthetases, glycosyltransferases and other enzymes have made molecular engineering design and outcomes more predictable.[18]

The molecular engineering of Daptomycin, the only marketed acidic lipopeptide antibiotic up to date (Figure 8), has seen many advances since its inception into clinical medicine in 2003.[19] It is an attractive target for combinatorial biosynthesis for many reasons: second generation derivatives are currently in the clinic for development;[20] Streptomyces roseosporus, the producer organism of daptomycin, is amenable to genetic manipulation;[21] the daptomycin biosynthetic gene cluster has been cloned, sequenced and expressed in a S. lividans;[20] the lipopeptide biosynthetic machinery has the potential to be interrupted by variations of natural precursors, as well as precursor-directed biosynthesis, gene deletion, genetic exchange, and module exchange;[21] the molecular engineering tools have been developed to facilitate the expression of the three individual NRPS genes from three different sites in the chromosome, using ermEp* for expression of two genes from ectopic loci;[22] other lipopeptide gene clusters, both related and unrelated to daptomycin, have been cloned and sequenced,[13] thus providing genes and modules to allow the generation of hybrid molecules;[21] derivatives can be afforded via chemoenzymatic synthesis;[23] and lastly, efforts in medicinal chemistry are able to further modify these products of molecular engineering.[20]

New derivatives of daptomycin (Figure 9) were originally generated by exchanging the third NRPS subunit (DptD) with the terminal subunits from the A54145 (Factor B1) or calcium-dependent antibiotic (CDA) pathways to create molecules containing Trp13, Ile13, or Val13.[24] Dpt D is responsible for incorporating the penultimate amino acid, 3-methyl-glutamic acid (3mGlu12), and the last amino acid, kynurenine (Kyn13), into the growing chain. This exchange was achieved without engineering the interpeptide dockingsites. These whole-subunit exchanges have been coupled combinatorially with the deletion of the Glu12-methyltransferase gene, with module exchanges at intradomain linker sites at Ala8 and Ser11, and with variations of natural fatty acid side chains to generate over seventy novel lipopeptides in significant quantities; most of these resultant lipopeptides have potent antibacterial activities.[13][24] Some of these compounds have in vitro antibacterial activities analogous to daptomycin. Further, one displayed ameliorated activity against an E. coli imp mutant that was defective in its ability to assemble its inherent lipopolysaccharide. A number of these compounds were produced in yields that spanned from 100 to 250 mg/liter; this, of course, opens up the possibility for successful scale-ups by means of fermentation techniques. Only a small percentage of the possible combinations of amino acids within the peptide core have been investigated thus far.[18]

Thus, the biosynthetic genes for daptomycin, a calcium-dependent antibiotic, have been cloned, sequenced, analyzed bioinformatically, genetically, and biochemically. The resultant information on the organization and expression of NRPS genes, among others, has been exploited and utilized to create combinatorial libraries of hybrid lipopeptide antibiotics related to daptomycin that have proven as effective antibiotics thus far in clinical trials .[25]

References[edit]

  1. ^ Woodworth JR, Nyhart EH, Brier GL, Wolny JD, Black HR (February 1992). = long&pmid = 1318678 "Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers". Antimicrob Agents Chemother. 36 (2): 318–25. PMC 188435. PMID 1318678. 
  2. ^ Tally FP, DeBruin MF (October 2000). "Development of daptomycin for gram-positive infections". J Antimicrob Chemother. 46 (4): 523–6. doi:10.1093/jac/46.4.523. PMID 11020247. 
  3. ^ Charles PG, Grayson ML (November 2004). "The dearth of new antibiotic development: why we should be worried and what we can do about it". Med J Aust. 181 (10): 549–53. PMID 15540967. 
  4. ^ Pogliano J, Pogliano, N, Silverman, JA (September 2012). "Daptomycin-Mediated Reorganization of Membrane Architecture Causes Mislocalization of Essential Cell Division Proteins". Journal of Bacteriology 194 (17): 4494–4504. PMID 22661688. 
  5. ^ Infect Dis Clin Pract 2013;21: 79-84.
  6. ^ Baltz RH. (Apr 2009). "Daptomycin: mechanisms of action and resistance, and biosynthetic engineering.". Curr Opin Chem Biol 13 (2): 144–151. doi:10.1016/j.cbpa.2009.02.031. PMID 19303806. 
  7. ^ Henken S, Bohling J, et al. (Feb 2010). "Efficacy Profiles of Daptomycin for Treatment of Invasive and Noninvasive Pulmonary Infections with Streptococcus pneumoniae". Antimicrob Agents Chemother 54 (2): 707–717. doi:10.1128/AAC.00943-09. PMID 19917756. 
  8. ^ Fowler VG, Boucher HW, Corey GR (Aug 2006). "Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus". N Engl J Med 355 (7): 653–65. doi:10.1056/NEJMoa053783. PMID 16914701. 
  9. ^ Davis SL, McKinnon PS, Hall LM (2007). "Daptomycin versus vancomycin for complicated skin and skin structure infections: clinical and economic outcomes.". Pharmacotherapy 27 (12): 1611–1618. doi:10.1592/phco.27.12.1611. PMID 18041881. 
  10. ^ Cubicin (daptomycin for injection) [homepage on the Internet]. Lexington (MA): Cubist Pharmaceuticals; c2003–06 [updated 2006 May 27; cited 2006 Aug 20]. Available from: http://www.cubicin.com/home.htm
  11. ^ Daptomycin. In: Klasco RK, editor. Drugdex system, vol. 129. Greenwood Village (CO): Thomson Micromedex; 2006.
  12. ^ Journal of Antimicrobial Chemotherapy. 63(6):1299-300, 2009 Jun.
  13. ^ a b c d Nguyen KT, Kau D, Gu JQ (September 2006). "A glutamic acid 3-methyltransferase encoded by an accessory gene locus important for daptomycin biosynthesis in Streptomyces roseosporus". Mol Microbiol. 61 (5): 1294–307. doi:10.1111/j.1365-2958.2006.05305.x. PMID 16879412. 
  14. ^ Miao V, Coëffet-Legal MF, Brian P (May 2005). "Daptomycin biosynthesis in Streptomyces roseosporus: cloning and analysis of the gene cluster and revision of peptide stereochemistry". Microbiology (Reading, Engl.) 151 (Pt 5): 1507–23. doi:10.1099/mic.0.27757-0. PMID 15870461. 
  15. ^ a b Steenbergen JN, Alder J, Thorne GM, Tally FP (March 2005). "Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections". J Antimicrob. Chemother. 55 (3): 283–8. doi:10.1093/jac/dkh546. PMID 15705644. 
  16. ^ a b Mchenney MA, Hosted TJ, Dehoff BS, Rosteck PR, Baltz RH (1 January 1998). "Molecular cloning and physical mapping of the daptomycin gene cluster from Streptomyces roseosporus". J Bacteriol. 180 (1): 143–51. PMC 106860. PMID 9422604. 
  17. ^ a b c d Fischbach MA, Walsh CT (August 2006). "Assembly-line enzymology for polyketide and nonribosomal Peptide antibiotics: logic, machinery, and mechanisms". Chem Rev. 106 (8): 3468–96. doi:10.1021/cr0503097. PMID 16895337. 
  18. ^ a b Baltz RH (December 2006). "Molecular engineering approaches to peptide, polyketide and other antibiotics". Nat Biotechnol. 24 (12): 1533–40. doi:10.1038/nbt1265. PMID 17160059. 
  19. ^ Baltz RH (February 1998). "Genetic manipulation of antibiotic-producing Streptomyces". Trends Microbiol. 6 (2): 76–83. doi:10.1016/S0966-842X(97)01161-X. PMID 9507643. 
  20. ^ a b c Baltz RH, Miao V, Wrigley SK (December 2005). "Natural products to drugs: daptomycin and related lipopeptide antibiotics". Nat Prod Rep 22 (6): 717–41. doi:10.1039/b416648p. PMID 16311632. 
  21. ^ a b c Baltz RH, Brian P, Miao V, Wrigley SK (February 2006). "Combinatorial biosynthesis of lipopeptide antibiotics in Streptomyces roseosporus". J Ind Microbiol Biotechnol. 33 (2): 66–74. doi:10.1007/s10295-005-0030-y. PMID 16193281. 
  22. ^ Nguyen KT, Ritz D, Gu JQ (November 2006). "Combinatorial biosynthesis of novel antibiotics related to daptomycin". Proc Natl Acad Sci USA. 103 (46): 17462–7. doi:10.1073/pnas.0608589103. PMC 1859951. PMID 17090667. 
  23. ^ Kopp F, Grünewald J, Mahlert C, Marahiel MA (September 2006). "Chemoenzymatic design of acidic lipopeptide hybrids: new insights into the structure-activity relationship of daptomycin and A54145". Biochemistry 45 (35): 10474–81. doi:10.1021/bi0609422. PMID 16939199. 
  24. ^ a b Miao V, Coëffet-Le Gal MF, Nguyen K (March 2006). "Genetic engineering in Streptomyces roseosporus to produce hybrid lipopeptide antibiotics". Chem Biol. 13 (3): 269–76. doi:10.1016/j.chembiol.2005.12.012. PMID 16638532. 
  25. ^ Baltz RH (2008). "Biosynthesis and genetic engineering of lipopeptide antibiotics related to daptomycin". Curr Top Med Chem 8 (8): 618–38. doi:10.2174/156802608784221497. PMID 18473888. 

External links[edit]

Category:Antibiotics Category:Eli Lilly and Company Category:Depsipeptides Category:Lipopeptides Category:Cyclic peptides Category:Peripheral membrane proteins Category:Chemical compounds found in Streptomyces species