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{{Short description|Antibiotic}}
{{Use dmy dates|date=March 2024}}
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 457630808
| image = Daptomycin Ball et al.svg
| width =
| alt =
| caption =
<!-- Clinical data -->
| pronounce =
| tradename = Cubicin, Cubicin RF, Dapzura RT
| Drugs.com = {{drugs.com|monograph|daptomycin}}
|
| DailyMedID = Daptomycin
|
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Daptomycin Use During Pregnancy | website=Drugs.com | date=3 December 2019 | url=https://www.drugs.com/pregnancy/daptomycin.html | access-date=28 August 2020}}</ref>
| pregnancy_category=
| routes_of_administration = [[Intravenous]]
| class =
| ATC_prefix = J01
| ATC_suffix = XX09
| ATC_supplemental =
<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | access-date=30 March 2024}}</ref>
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment = <ref>{{cite web | title=Cubicin 350 mg powder for solution for injection or infusion - Summary of Product Characteristics (SmPC) | website=(emc) | date=24 August 2018 | url=https://www.medicines.org.uk/emc/product/177/smpc | access-date=28 August 2020}}</ref>
| legal_US = Rx-only
| legal_US_comment = <ref name="Cubicin FDA label">{{cite web | title=Cubicin- daptomycin injection, powder, lyophilized, for solution | website=[[DailyMed]] | date=18 December 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a7975871-46a6-4e9b-a8b5-38bfcb465f0e | access-date=28 August 2020}}</ref><ref>{{cite web | title=Cubicin RF- daptomycin injection, powder, lyophilized, for solution | website=DailyMed | date=18 December 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0b1a8885-2198-4a0e-8105-0c76c1cba6c2 | access-date=28 August 2020}}</ref>
| legal_EU = Rx-only
| legal_EU_comment = <ref>{{cite web | title=Cubicin | website=European Medicines Agency | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/cubicin | access-date=28 August 2020}}</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->
<!-- Pharmacokinetic data -->
| bioavailability = n/a
| protein_bound = 90–95%
| metabolism =
| metabolites =
| onset =
| elimination_half-life = 7–11 hours (up to 28 hours in renal impairment)
| duration_of_action =
| excretion = [[Kidney]] (78%; primarily as unchanged drug); faeces (5.7%)
<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 103060-53-3
| CAS_supplemental =
| PubChem = 16129629
| IUPHAR_ligand =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00080
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| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 508162
| NIAID_ChemDB =
|
|
<!-- Chemical and physical data -->
| IUPAC_name = ''N''-Decanoyl-<small>L</small>-tryptophyl-<small>L</small>-asparaginyl-<small>L</small>-aspartyl-<small>L</small>-threonylglycyl-<small>L</small>-ornithyl-<small>L</small>-aspartyl-<small>D</small>-alanyl-<small>L</small>-aspartylglycyl-<small>D</small>-seryl-''threo''-3-methyl-<small>L</small>-glutamyl-3-anthraniloyl-<small>L</small>-alanine[egr]<sub>1</sub>-lactone
| C=72 | H=101 | N=17 | O=26
| SMILES =
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C72H101N17O26/c1-5-6-7-8-9-10-11-22-53(93)81-44(25-38-31-76-42-20-15-13-17-39(38)42)66(108)84-45(27-52(75)92)67(109)86-48(30-59(102)103)68(110)89-61-37(4)115-72(114)49(26-51(91)40-18-12-14-19-41(40)74)87-71(113)60(35(2)24-56(96)97)88-69(111)50(34-90)82-55(95)32-77-63(105)46(28-57(98)99)83-62(104)36(3)79-65(107)47(29-58(100)101)85-64(106)43(21-16-23-73)80-54(94)33-78-70(61)112/h12-15,17-20,31,35-37,43-50,60-61,76,90H,5-11,16,21-30,32-34,73-74H2,1-4H3,(H2,75,92)(H,77,105)(H,78,112)(H,79,107)(H,80,94)(H,81,93)(H,82,95)(H,83,104)(H,84,108)(H,85,106)(H,86,109)(H,87,113)(H,88,111)(H,89,110)(H,96,97)(H,98,99)(H,100,101)(H,102,103)/t35-,36-,37-,43+,44+,45+,46+,47+,48+,49+,50-,60+,61+/m1/s1 -->
| StdInChI_comment =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = DOAKLVKFURWEDJ-RWDRXURGSA-N
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}}
{{Infobox protein family
| Symbol = N/A
| drug_name =
| image = Mechanism of Daptomycin Action.jpg
| width = 300px
| caption = 1. Daptomycin binds and inserts into the cell membrane. 2. It aggregates in the membrane. 3. It alters the shape of the membrane to form a hole, allowing ions in and out of the cell easily.
| Pfam =
| Pfam_clan =
| InterPro =
| SMART =
| PROSITE =
| MEROPS =
| SCOP =
| TCDB = 1.D.15
| OPM family = 163
| OPM protein = 1t5n
| CAZy =
| CDD =
}}
'''Daptomycin''', sold under the brand name '''Cubicin''' among others, is a [[lipopeptide]] [[antibiotic]] used in the treatment of systemic and life-threatening infections caused by [[Gram-positive]] organisms.
Daptomycin was removed from the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]] in 2019.<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | year = 2019 | title = Executive summary: the selection and use of essential medicines 2019: report of the 22nd WHO Expert Committee on the selection and use of essential medicines | publisher = World Health Organization | location = Geneva | author-link = World Health Organization | hdl = 10665/325773 | id = WHO/MVP/EMP/IAU/2019.05. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref><ref>{{cite book | vauthors = ((World Health Organization)) | year = 2019 | title = The selection and use of essential medicines: report of the WHO Expert Committee on Selection and Use of Essential Medicines, 2019 (including the 21st WHO Model List of Essential Medicines and the 7th WHO Model List of Essential Medicines for Children) | publisher = World Health Organization | location = Geneva | author-link = World Health Organization | hdl = 10665/330668 | id = WHO technical report series;1021 | hdl-access=free | isbn = 9789241210300 | issn = 0512-3054 }}</ref> The World Health Organization classifies daptomycin as critically important for human medicine.<ref>{{cite book | vauthors=((World Health Organization)) | year=2019 | title=Critically important antimicrobials for human medicine | edition=6th revision | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | hdl=10665/312266 | isbn=9789241515528 | hdl-access=free }}</ref>
==Medical uses==
In the United States, daptomycin is [[Indication (medicine)|indicated]] for use in adults for [[skin and skin structure infection]]s caused by Gram-positive infections, ''S. aureus'' bacteraemia, and right-sided ''S. aureus'' [[endocarditis]].<ref name="Cubicin FDA label" /> It binds avidly to [[pulmonary surfactant]], so cannot be used in the treatment of pneumonia.<ref>{{cite journal | vauthors = Baltz RH | title = Daptomycin: mechanisms of action and resistance, and biosynthetic engineering | journal = Current Opinion in Chemical Biology | volume = 13 | issue = 2 | pages = 144–151 | date = April 2009 | pmid = 19303806 | doi = 10.1016/j.cbpa.2009.02.031 }}</ref> There seems to be a difference in working daptomycin on hematogenous pneumonia.<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = Efficacy profiles of daptomycin for treatment of invasive and noninvasive pulmonary infections with Streptococcus pneumoniae | journal = Antimicrobial Agents and Chemotherapy | volume = 54 | issue = 2 | pages = 707–717 | date = February 2010 | pmid = 19917756 | pmc = 2812129 | doi = 10.1128/AAC.00943-09 }}</ref>
== Adverse effects ==
Common adverse drug reactions associated with daptomycin therapy include:<ref name="Cubicin FDA label" /><ref name="MicromedexDrugdex">{{cite book | chapter = Daptomycin | veditors = Klasco RK | title = Drugdex System | volume = 129 | date = 2006 }}</ref>
* Cardiovascular: [[hypotension|low blood pressure]], [[hypertension|high blood pressure]], [[edema|swelling]]
* Central nervous system: insomnia
* Dermatological: rash
* Gastrointestinal: diarrhea, abdominal pain
* Hematological: [[eosinophilia]]
* Respiratory: [[dyspnea]]
* Other: injection site reactions, fever, [[hypersensitivity]]
Less common, but serious adverse events reported in the literature include
* Hepatotoxicity:<ref>{{cite journal | vauthors = Mo Y, Nehring F, Jung AH, Housman ST | title = Possible Hepatotoxicity Associated With Daptomycin: A Case Report and Literature Review | journal = Journal of Pharmacy Practice | volume = 29 | issue = 3 | pages = 253–256 | date = June 2016 | pmid = 26763341 | doi = 10.1177/0897190015625403 | s2cid = 26176155 }}</ref> [[elevated transaminases]]
* Nephrotoxicity:<ref>{{cite journal | vauthors = Kazory A, Dibadj K, Weiner ID | title = Rhabdomyolysis and acute renal failure in a patient treated with daptomycin | journal = The Journal of Antimicrobial Chemotherapy | volume = 57 | issue = 3 | pages = 578–579 | date = March 2006 | pmid = 16410267 | doi = 10.1093/jac/dki476 | doi-access = }}</ref> [[acute kidney injury]] from [[rhabdomyolysis]]
Also, [[myopathy]] and [[rhabdomyolysis]] have been reported in patients simultaneously taking [[statin]]s,<ref name="pmid19346518">{{cite journal | vauthors = Odero RO, Cleveland KO, Gelfand MS | title = Rhabdomyolysis and acute renal failure associated with the co-administration of daptomycin and an HMG-CoA reductase inhibitor | journal = The Journal of Antimicrobial Chemotherapy | volume = 63 | issue = 6 | pages = 1299–1300 | date = June 2009 | pmid = 19346518 | doi = 10.1093/jac/dkp127 | doi-access = free }}</ref> 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.{{cn|date=February 2023}}
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 cases were all older than 60 and symptoms appeared within two weeks of initiation of therapy.{{cn|date=February 2023}}
== Pharmacology ==
===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.<ref name="Pogliano 2012">{{cite journal | vauthors = Pogliano J, Pogliano N, Silverman JA | title = Daptomycin-mediated reorganization of membrane architecture causes mislocalization of essential cell division proteins | journal = Journal of Bacteriology | volume = 194 | issue = 17 | pages = 4494–4504 | date = September 2012 | pmid = 22661688 | pmc = 3415520 | doi = 10.1128/JB.00011-12 }}</ref>
It has been proposed that the formation of spherical micelles<ref>{{cite journal | vauthors = Kirkham S, Castelletto V, Hamley IW, Inoue K, Rambo R, Reza M, Ruokolainen J | title = Self-Assembly of the Cyclic Lipopeptide Daptomycin: Spherical Micelle Formation Does Not Depend on the Presence of Calcium Chloride | journal = ChemPhysChem | volume = 17 | issue = 14 | pages =
== Microbiology ==
{{expand section|date=January 2015}}
Daptomycin is bactericidal against Gram-positive bacteria only. It has proven ''in vitro'' activity against [[Enterococcus|enterococci]] (including [[glycopeptide]]-resistant enterococci (GRE)), [[Staphylococcus|staphylococci]] (including [[methicillin-resistant Staphylococcus aureus|methicillin-resistant ''Staphylococcus aureus'']]), [[Streptococcus|streptococci]],<ref>{{cite journal | vauthors = Shoemaker DM, Simou J, Roland WE | title = A review of daptomycin for injection (Cubicin) in the treatment of complicated skin and skin structure infections | journal = Therapeutics and Clinical Risk Management | volume = 2 | issue = 2 | pages = 169–174 | date = June 2006 | pmid = 18360590 | pmc = 1661656 | doi = 10.2147/tcrm.2006.2.2.169 | doi-access = free }}</ref> [[Corynebacterium|corynebacteria]] and stationary-phase ''[[Borrelia burgdorferi]]'' persisters.<ref name="FengWeitner2016">{{
== Daptomycin resistance ==
Daptomycin resistance is still uncommon,{{when|date=July 2020}} but has been increasingly reported in GRE, starting in Korea in 2005, in Europe in 2010, in Taiwan 2011, and in the
It has been suggested that co-administration of daptomycin with at least another active antibiotic might help prevent the emergence of resistance and increase the bactericidal effect.<ref>{{cite journal | vauthors = Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta JP, Del Zotti F, Dulgheru R, El Khoury G, Erba PA, Iung B, Miro JM, Mulder BJ, Plonska-Gosciniak E, Price S, Roos-Hesselink J, Snygg-Martin U, Thuny F, Tornos Mas P, Vilacosta I, Zamorano JL | display-authors = 6 | title = 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM) | journal = European Heart Journal | volume = 36 | issue = 44 | pages = 3075–3128 | date = November 2015 | pmid = 26320109 | doi = 10.1093/eurheartj/ehv319 | doi-access = free }}</ref> Data from ''in vitro'' and ''in vivo'' studies suggest that a tailored approach should be used taking into account both the causative agent and the site of infection.<ref>{{cite journal | vauthors = Antonello RM, Canetti D, Riccardi N | title = Daptomycin synergistic properties from in vitro and in vivo studies: a systematic review | journal = The Journal of Antimicrobial Chemotherapy | volume = 78 | issue = 1 | pages = 52–77 | date = December 2022 | pmid = 36227704 | doi = 10.1093/jac/dkac346 }}</ref>
==
{{expand section|date=January 2015}}
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''.<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus | journal = The New England Journal of Medicine | volume = 355 | issue = 7 | pages =
In Phase III clinical trials, limited data showed daptomycin to be associated with poor outcomes in patients with left-sided endocarditis.{{Citation needed|date=September 2012}} Daptomycin has not been studied in patients with [[prosthetic heart valve|prosthetic valve]] endocarditis or meningitis.<ref name=Cubist2005>{{cite web | url = http://cubicin.com/ | title = Cubicin (daptomycin for injection) | publisher = Cubist Pharmaceuticals | access-date = 17 March 2018 | archive-date = 11 April 2021 | archive-url = https://web.archive.org/web/20210411015507/https://www.cubicin.com/ | url-status = dead }}</ref>
== Biosynthesis ==
[[File:Dap.52.png|thumb|'''Figures
[[File:nbt1265-F2.png|thumb|'''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).<ref name=Nguyen>{{cite journal | vauthors = Nguyen KT, Kau D, Gu JQ, Brian P, Wrigley SK, Baltz RH, Miao V | title = A glutamic acid 3-methyltransferase encoded by an accessory gene locus important for daptomycin biosynthesis in Streptomyces roseosporus | journal = Molecular Microbiology | volume = 61 | issue = 5 | pages =
]]
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<ref name=Nguyen/>]]
Daptomycin is a cyclic lipopeptide antibiotic produced by ''[[Streptomyces
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.<ref name=Mchenney>{{cite journal | vauthors = Mchenney MA, Hosted TJ, Dehoff BS, Rosteck PR, Baltz RH | title = Molecular cloning and physical mapping of the daptomycin gene cluster from Streptomyces roseosporus | journal = Journal of Bacteriology | volume = 180 | issue = 1 | pages = 143–151 | date = January 1998 | pmid = 9422604 | pmc = 106860 | doi = 10.1128/JB.180.1.143-151.1998 }}</ref> 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.<ref name=Mchenney/>
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.{{medcn|date=September 2019}}
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.<ref name=Fischbach>{{cite journal | vauthors = Fischbach MA, Walsh CT | title = Assembly-line enzymology for polyketide and nonribosomal Peptide antibiotics: logic, machinery, and mechanisms | journal = Chemical Reviews | volume = 106 | issue = 8 | pages = 3468–3496 | date = August 2006 | pmid = 16895337 | doi = 10.1021/cr0503097 }}</ref> 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.<ref name=Fischbach/>
The first module has a three-domain C-A-T organization; these often occur in assembly lines that make N-acylated peptides.<ref name=Fischbach/> 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.{{medcn|date=September 2019}}
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).<ref name=Steenbergen/> 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.<ref name=Fischbach/>
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.<ref>{{cite journal | vauthors = Baltz RH | title = Genetic manipulation of antibiotic-producing Streptomyces | journal = Trends in Microbiology | volume = 6 | issue = 2 | pages = 76–83 | date = February 1998 | pmid = 9507643 | doi = 10.1016/S0966-842X(97)01161-X }}</ref> It is an attractive target for combinatorial biosynthesis for many reasons: second generation derivatives are currently in the clinic for development;<ref name=Baltz16311632>{{cite journal | vauthors = Baltz RH, Miao V, Wrigley SK | title = Natural products to drugs: daptomycin and related lipopeptide antibiotics | journal = Natural Product Reports | volume = 22 | issue = 6 | pages = 717–741 | date = December 2005 | pmid = 16311632 | doi = 10.1039/b416648p }}</ref>
''Streptomyces roseosporus'', the producer organism of daptomycin, is amenable to genetic manipulation;<ref name=Baltz16193281>{{cite journal | vauthors = Baltz RH, Brian P, Miao V, Wrigley SK | title = Combinatorial biosynthesis of lipopeptide antibiotics in Streptomyces roseosporus | journal = Journal of Industrial Microbiology & Biotechnology | volume = 33 | issue = 2 | pages = 66–74 | date = February 2006 | pmid = 16193281 | doi = 10.1007/s10295-005-0030-y | s2cid = 10856890 | doi-access = free }}</ref> the daptomycin biosynthetic gene cluster has been cloned, sequenced, and expressed in ''S. lividans'';<ref name=Baltz16311632/> 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;<ref name=Baltz16193281/> 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;<ref>{{cite journal | vauthors = Nguyen KT, Ritz D, Gu JQ, Alexander D, Chu M, Miao V, Brian P, Baltz RH | display-authors = 6 | title = Combinatorial biosynthesis of novel antibiotics related to daptomycin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 46 | pages = 17462–17467 | date = November 2006 | pmid = 17090667 | pmc = 1859951 | doi = 10.1073/pnas.0608589103 | doi-access = free | bibcode = 2006PNAS..10317462N }}</ref> other lipopeptide gene clusters, both related and unrelated to daptomycin, have been cloned and sequenced,<ref name=Nguyen/> thus providing genes and modules to allow the generation of hybrid molecules;<ref name=Baltz16193281/> derivatives can be afforded via chemoenzymatic synthesis;<ref>{{cite journal | vauthors = Kopp F, Grünewald J, Mahlert C, Marahiel MA | title = Chemoenzymatic design of acidic lipopeptide hybrids: new insights into the structure-activity relationship of daptomycin and A54145 | journal = Biochemistry | volume = 45 | issue = 35 | pages = 10474–10481 | date = September 2006 | pmid = 16939199 | doi = 10.1021/bi0609422 }}</ref> and lastly, efforts in medicinal chemistry are able to further modify these products of molecular engineering.<ref name=Baltz16311632/>
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.<ref name=Miao/> ''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.<ref name=Nguyen/><ref name=Miao>{{cite journal | vauthors = 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 | display-authors = 6 | title = Genetic engineering in Streptomyces roseosporus to produce hybrid lipopeptide antibiotics | journal = Chemistry & Biology | volume = 13 | issue = 3 | pages = 269–276 | date = March 2006 | pmid = 16638532 | doi = 10.1016/j.chembiol.2005.12.012 | doi-access = }}</ref> 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.<ref name=Baltz17160059>{{cite journal | vauthors = Baltz RH | title = Molecular engineering approaches to peptide, polyketide and other antibiotics | journal = Nature Biotechnology | volume = 24 | issue = 12 | pages = 1533–1540 | date = December 2006 | pmid = 17160059 | doi = 10.1038/nbt1265 | s2cid = 30003086 }}</ref>
== History ==
Daptomycin, originally designated as LY 146032, was discovered by researchers at [[Eli Lilly and Company]] in the late 1980s from the [[actinomycete]] ''[[Streptomyces roseosporus]]''. LY 146032 showed promise in phase I/II [[clinical trial]]s 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]].<ref>{{cite journal | vauthors = Eisenstein BI, Oleson FB, Baltz RH | title = Daptomycin: from the mountain to the clinic, with essential help from Francis Tally, MD | journal = Clinical Infectious Diseases | volume = 50 | issue = Supplement_1 | pages = S10–S15 | date = January 2010 | pmid = 20067387 | doi = 10.1086/647938 | publication-date = 1 February 2010 | doi-access = free }}</ref><ref name=Tally2000>{{cite journal | vauthors = Tally FP, DeBruin MF | title = Development of daptomycin for gram-positive infections | journal = The Journal of Antimicrobial Chemotherapy | volume = 46 | issue = 4 | pages = 523–526 | date = October 2000 | pmid = 11020247 | doi = 10.1093/jac/46.4.523 | doi-access = free }}</ref>
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]], the previous licensee.<ref name="Tally2000" /><ref name="Charles 2004">{{cite journal | vauthors = Charles PG, Grayson ML | title = The dearth of new antibiotic development: why we should be worried and what we can do about it | journal = The Medical Journal of Australia | volume = 181 | issue = 10 | pages = 549–553 | date = November 2004 | pmid = 15540967 | doi = 10.5694/j.1326-5377.2004.tb06444.x | s2cid = 18526863 }}</ref>
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== References ==
{{Reflist
== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Giuliani A, Pirri G, Nicoletto S |title=Antimicrobial peptides: an overview of a promising class of therapeutics |journal=Cent. Eur. J. Biol. |volume=2 |issue=1 |pages=1–33 |year=2007 |doi=10.2478/s11535-007-0010-5|doi-access=free }}
* {{cite journal | vauthors = Pirri G, Giuliani A, Nicoletto S, Pizutto L, Rinaldi A |title=Lipopeptides as anti-infectives: a practical perspective |journal=Cent. Eur. J. Biol. |volume=4 |issue=3 |pages=258–273 |year=2009 |doi=10.2478/s11535-009-0031-3|doi-access=free |url=https://www.openaccessrepository.it/record/118487/files/fulltext.pdf }}
* {{cite journal | vauthors = Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI | title = The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections | journal = Clinical Infectious Diseases | volume = 38 | issue = 12 | pages = 1673–1681 | date = June 2004 | pmid = 15227611 | doi = 10.1086/420818 | collaboration = Daptomycin 98-01 and 99-01 Investigators | doi-access = free }}
{{refend}}
== External links ==
* {{cite web | title=FDA Rationale for Recognition Decision: Daptomycin | website=U.S. [[Food and Drug Administration]] (FDA) | date=28 August 2020 | url=https://www.fda.gov/drugs/development-resources/fda-rationale-recognition-decision-daptomycin }}
{{Other antibacterials}}
{{Authority control}}
[[Category:Antibiotics]]
[[Category:Cyclic peptides]]
[[Category:Depsipeptides]]
[[Category:Drugs developed by Eli Lilly and Company
[[Category:
[[Category:Lipopeptides]]
[[Category:Drugs developed by Merck & Co.
[[Category:Peripheral membrane proteins]]
[[Category:Polypeptide antibiotics]]
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