Wed . 19 Apr 2019

Daptomycin

daptomycin, daptomycin antibiotic
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 multiple drug-resistant bacteria It is marketed in the United States under the trade name Cubicin by Cubist Pharmaceuticals

Contents

  • 1 History
  • 2 Mechanism of action
  • 3 Microbiology
  • 4 Daptomycin resistance
  • 5 Clinical use
    • 51 Indications
    • 52 Efficacy
    • 53 Dosage and presentation
    • 54 Adverse effects
  • 6 Biosynthesis
  • 7 References
  • 8 External links

History

Daptomycin, originally designated as 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 US 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, the previous licensee

Mechanism of action

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

1 Daptomycin binds and inserts into the cell membrane 2 Aggregates in the cell membrane 3 Alters the shape of the cell membrane to form a hole in the cell, allowing ions in and out of the cell easily

It has been proposed that the formation of spherical micelles by Daptomycin may affect the mode of action

Microbiology

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, corynebacteria and stationary-phase Borrelia burgdorferi persisters

Daptomycin resistance

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 nine cases have been reported from 2007 to 2011 Daptomycin resistance emerged in five of the six cases while they were treated The mechanism of resistance is unknown A 4 million year-old strain of Paenibacillus isolated from soil samples in Lechuguilla Cave was found to be naturally resistant to daptomycin

Clinical use

Indications

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

Efficacy

Daptomycin has been shown to be non-inferior to standard therapies nafcillin, oxacillin, flucloxacillin or vancomycin in the treatment of bacteraemia and right-sided endocarditis caused by S aureus A study in Detroit, Michigan compared 53 patients treated for suspected MRSA skin or soft tissue infection with daptomycin against vancomycin, showing faster recovery 4 versus 7 days with daptomycin

In phase III clinical trials, limited data showed daptomycin to be associated with poor outcomes in patients with left-sided endocarditis Daptomycin has not been studied in patients with prosthetic valve endocarditis or meningitis

Dosage and presentation

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 with a creatinine clearance of less than 30 ml/min No information is 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- or 350-mg cake that must be reconstituted with normal saline prior to use

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

Adverse effects

Common adverse drug reactions associated with daptomycin therapy include:

  • Cardiovascular: low blood pressure, high blood pressure, swelling
  • Central nervous system: insomnia
  • Dermatological: rash
  • Gastrointestinal: diarrhea, abdominal pain
  • Hematological: eosinophilia
  • Respiratory: dyspnea
  • Other: injection site reactions, fever, hypersensitivity

Also, myopathy and rhabdomyolysis have been reported in patients simultaneously taking statins, 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 Creatine kinase levels are usually checked regularly while individuals undergo daptomycin therapy

In July 2010, the FDA issued a warning that daptomycin could cause life-threatening eosinophilic pneumonia The FDA said 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

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 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

Daptomycin is a cyclic lipopeptide antibiotic produced by Streptomyces roseosporus Daptomycin consists of 13 amino acids, 10 of which are arranged in a cyclic fashion, and three on an exocyclic tail Two nonproteinogenic 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 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 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 nonproteinogenic amino acids L-3-methylglutamic acid and Kyn; they are located next to the NRPS genes

The decanoic acid portion of daptomycin is synthesized by fatty acid synthase machinery Figure 2 Post-translational 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 provide a thiol on which the substrate and acyl chains are covalently bound 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 domain, followed by dehydration to the olefin catalyzed by a dehydratase domain, and finally reduction to the methylene catalyzed by an enoylreductase 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 an 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 Within each module are catalytic domains that carry out the elongation of the growing peptidyl chain The growing peptide is covalently tethered to a thiolation domain; here it is termed the peptidyl carrier protein, 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 by a PPTase, attaching a flexible phosphopantetheine arm to a conserved serine residue An adenylation 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 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 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

The first module has a three-domain C-A-T organization; these often occur in assembly lines that make N-acylated peptides 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-asparagine, 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 nonproteinogenic amino acids, L-3-methylglutamic acid mGlu and Kyn, which is only known thus far to daptomycin, into the growing peptide Figure 6 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 domain catalyzes chain termination and release of the mature lipopeptide

The molecular engineering of daptomycin, the only marketed acidic lipopeptide antibiotic to date Figure 8, has seen many advances since its inception into clinical medicine in 2003 It is an attractive target for combinatorial biosynthesis for many reasons: second generation derivatives are currently in the clinic for development; Streptomyces roseosporus, the producer organism of daptomycin, is amenable to genetic manipulation; the daptomycin biosynthetic gene cluster has been cloned, sequenced, and expressed in S lividans; 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; 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; other lipopeptide gene clusters, both related and unrelated to daptomycin, have been cloned and sequenced, thus providing genes and modules to allow the generation of hybrid molecules; derivatives can be afforded via chemoenzymatic synthesis; and lastly, efforts in medicinal chemistry are able to further modify these products of molecular engineering

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 pathways to create molecules containing Trp13, Ile13, or Val13 dptD is responsible for incorporating the penultimate amino acid, 3-methyl-glutamic acid 3mGlu12, and the last amino acid, Kyn13, into the chain This exchange was achieved without engineering the interpeptide docking sites These whole-subunit exchanges have been coupled 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 70 novel lipopeptides in significant quantities; most of these resultant lipopeptides have potent antibacterial activities 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 fermentation techniques Only a small percentage of the possible combinations of amino acids within the peptide core have been investigated thus far

References

  1. ^ Woodworth JR, Nyhart EH, Brier GL, Wolny JD, Black HR February 1992 "Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers" Antimicrobial Agents and Chemotherapy 36 2: 318–25 doi:101128/aac362318 PMC 188435  PMID 1318678 
  2. ^ Tally FP, DeBruin MF October 2000 "Development of daptomycin for gram-positive infections" The Journal of Antimicrobial Chemotherapy 46 4: 523–6 doi:101093/jac/464523 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" The Medical Journal of Australia 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: 4494–504 doi:101128/JB00011-12 PMC 3415520  PMID 22661688 
  5. ^ Kirkham S, Castelletto V, Hamley IW, Inoue K, Rambo R, Reza M, Ruokolainen J July 2016 "Self-Assembly of the Cyclic Lipopeptide Daptomycin: Spherical Micelle Formation Does Not Depend on the Presence of Calcium Chloride" Chemphyschem 17 14: 2118–22 doi:101002/cphc201600308 PMID 27043447 
  6. ^ Cleveland KO, Gelfand MS May 2013 "Daptomycin-Nonsusceptible Enterococcal Infections" Infectious Diseases in Clinical Practice 21 3: 213 doi:101097/IPC0b013e31828875fc 
  7. ^ Pawlowski AC, Wang W, Koteva K, Barton HA, McArthur AG, Wright GD December 2016 "A diverse intrinsic antibiotic resistome from a cave bacterium" Nature Communications 7: 13803 doi:101038/ncomms13803 PMID 27929110 
  8. ^ Baltz RH April 2009 "Daptomycin: mechanisms of action and resistance, and biosynthetic engineering" Current Opinion in Chemical Biology 13 2: 144–51 doi:101016/jcbpa200902031 PMID 19303806 
  9. ^ Henken S, Bohling J, Martens-Lobenhoffer J, Paton JC, Ogunniyi AD, Briles DE, Salisbury VC, Wedekind D, Bode-Böger SM, Welsh T, Bange FC, Welte T, Maus UA February 2010 "Efficacy profiles of daptomycin for treatment of invasive and noninvasive pulmonary infections with Streptococcus pneumoniae" Antimicrobial Agents and Chemotherapy 54 2: 707–17 doi:101128/AAC00943-09 PMC 2812129  PMID 19917756 
  10. ^ Fowler VG, Boucher HW, Corey GR, Abrutyn E, Karchmer AW, Rupp ME, Levine DP, Chambers HF, Tally FP, Vigliani GA, Cabell CH, Link AS, DeMeyer I, Filler SG, Zervos M, Cook P, Parsonnet J, Bernstein JM, Price CS, Forrest GN, Fätkenheuer G, Gareca M, Rehm SJ, Brodt HR, Tice A, Cosgrove SE August 2006 "Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus" The New England Journal of Medicine 355 7: 653–65 doi:101056/NEJMoa053783 PMID 16914701 
  11. ^ Davis SL, McKinnon PS, Hall LM, Delgado G, Rose W, Wilson RF, Rybak MJ December 2007 "Daptomycin versus vancomycin for complicated skin and skin structure infections: clinical and economic outcomes" Pharmacotherapy 27 12: 1611–8 doi:101592/phco27121611 PMID 18041881 
  12. ^ "Cubicin daptomycin for injection" Cubist Pharmaceuticals 
  13. ^ "wwwaccessdatafdagov" PDF 
  14. ^ Daptomycin In: Klasco RK, editor Drugdex system, vol 129 Greenwood Village CO: Thomson Micromedex; 2006
  15. ^ Journal of Antimicrobial Chemotherapy 636:1299-300, 2009 Jun
  16. ^ a b c d Nguyen KT, Kau D, Gu JQ, Brian P, Wrigley SK, Baltz RH, Miao V September 2006 "A glutamic acid 3-methyltransferase encoded by an accessory gene locus important for daptomycin biosynthesis in Streptomyces roseosporus" Molecular Microbiology 61 5: 1294–307 doi:101111/j1365-2958200605305x PMID 16879412 
  17. ^ Miao V, Coëffet-Legal MF, Brian P, Brost R, Penn J, Whiting A, Martin S, Ford R, Parr I, Bouchard M, Silva CJ, Wrigley SK, Baltz RH May 2005 "Daptomycin biosynthesis in Streptomyces roseosporus: cloning and analysis of the gene cluster and revision of peptide stereochemistry" Microbiology 151 Pt 5: 1507–23 doi:101099/mic027757-0 PMID 15870461 
  18. ^ a b Steenbergen JN, Alder J, Thorne GM, Tally FP March 2005 "Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections" The Journal of Antimicrobial Chemotherapy 55 3: 283–8 doi:101093/jac/dkh546 PMID 15705644 
  19. ^ a b Mchenney MA, Hosted TJ, Dehoff BS, Rosteck PR, Baltz RH January 1998 "Molecular cloning and physical mapping of the daptomycin gene cluster from Streptomyces roseosporus" Journal of Bacteriology 180 1: 143–51 PMC 106860  PMID 9422604 
  20. ^ a b c d Fischbach MA, Walsh CT August 2006 "Assembly-line enzymology for polyketide and nonribosomal Peptide antibiotics: logic, machinery, and mechanisms" Chemical Reviews 106 8: 3468–96 doi:101021/cr0503097 PMID 16895337 
  21. ^ Baltz RH February 1998 "Genetic manipulation of antibiotic-producing Streptomyces" Trends in Microbiology 6 2: 76–83 doi:101016/S0966-842X9701161-X PMID 9507643 
  22. ^ a b c Baltz RH, Miao V, Wrigley SK December 2005 "Natural products to drugs: daptomycin and related lipopeptide antibiotics" Natural Product Reports 22 6: 717–41 doi:101039/b416648p PMID 16311632 
  23. ^ a b c Baltz RH, Brian P, Miao V, Wrigley SK February 2006 "Combinatorial biosynthesis of lipopeptide antibiotics in Streptomyces roseosporus" Journal of Industrial Microbiology & Biotechnology 33 2: 66–74 doi:101007/s10295-005-0030-y PMID 16193281 
  24. ^ Nguyen KT, Ritz D, Gu JQ, Alexander D, Chu M, Miao V, Brian P, Baltz RH November 2006 "Combinatorial biosynthesis of novel antibiotics related to daptomycin" Proceedings of the National Academy of Sciences of the United States of America 103 46: 17462–7 doi:101073/pnas0608589103 PMC 1859951  PMID 17090667 
  25. ^ 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:101021/bi0609422 PMID 16939199 
  26. ^ a b Miao V, Coëffet-Le Gal MF, Nguyen K, Brian P, Penn J, Whiting A, Steele J, Kau D, Martin S, Ford R, Gibson T, Bouchard M, Wrigley SK, Baltz RH March 2006 "Genetic engineering in Streptomyces roseosporus to produce hybrid lipopeptide antibiotics" Chemistry & Biology 13 3: 269–76 doi:101016/jchembiol200512012 PMID 16638532 
  27. ^ Baltz RH December 2006 "Molecular engineering approaches to peptide, polyketide and other antibiotics" Nature Biotechnology 24 12: 1533–40 doi:101038/nbt1265 PMID 17160059 

External links

  • Giuliani A, Pirri G, Nicoletto S 2007 "Antimicrobial peptides: an overview of a promising class of therapeutics" Cent Eur J Biol 2 1: 1–33 doi:102478/s11535-007-0010-5 CS1 maint: Uses authors parameter link
  • Pirri G, Giuliani A, Nicoletto S, Pizutto L, Rinaldi A 2009 "Lipopeptides as anti-infectives: a practical perspective" Cent Eur J Biol 4 3: 258–273 doi:102478/s11535-009-0031-3 CS1 maint: Uses authors parameter link
  • Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI June 2004 "The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections" Clinical Infectious Diseases 38 12: 1673–81 doi:101086/420818 PMID 15227611 
  • PubChem Substance ID
  • New ATC Codes from WHO
  • UMich Orientation of Proteins in Membranes families/superfamily-172 - Orientations of daptomycin and tsushimycin in membrane

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