Daptomycin: Difference between revisions

{{Drugbox

| verifiedrevid = 387947294

| IUPAC_name = ''N''-decanoyl-L-tryptophyl-L-asparaginyl-L-aspartyl-L-threonylglycyl-<BR>L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-''threo'' -3-methyl-L-glutamyl-3-anthraniloyl-L-alanine[egr]₁-lactone

| width = 300px

<!--Clinical data-->

| tradename = Cubicin

| pregnancy_US = B

| legal_US = Rx-only

<!--Pharmacokinetic data-->

| metabolism = Renal (speculative)<ref>{{cite journal | author = Woodworth JR, Nyhart EH, Brier GL, Wolny JD, Black HR | title = Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers | journal = Antimicrob Agents Chemother. | volume = 36 | issue = 2 | pages = 318–25 | year = 1992 | month = February | pmid = 1318678 | pmc = 188435 | url = http://aac.asm.org/cgi/pmidlookup?view = long&pmid = 1318678 | doi = }}</ref>

| excretion = [[Kidney|Renal]] (78%; primarily as unchanged drug); Faeces (5.7%)

<!--Identifiers-->

| CASNo_Ref = {{cascite|correct|CAS}}

| ATC_prefix = J01

| ATC_suffix = XX09

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| UNII_Ref = {{fdacite|changed|FDA}}

| KEGG = <!-- blanked - oldvalue: D01080 -->

| ChEMBL = <!-- blanked - oldvalue: 508162 -->

| C=72 | H=101 | N=17 | O=26

| molecular_weight = 1619.7086 g/mol

| InChI = 1/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

| InChIKey = DOAKLVKFURWEDJ-RWDRXURGBK

| 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

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

'''Daptomycin''' is a novel [[lipopeptide]] [[antibiotic]] used in the treatment of certain infections caused by [[Gram-positive]] organisms. It is a naturally occurring compound found in the soil [[saprotroph]] ''[[Streptomyces roseosporus]]''. Its distinct mechanism of action means that it may be useful in treating infections caused by multi-resistant bacteria. It is marketed in the United States under the trade name '''Cubicin''' ([[Cubist Pharmaceuticals]]).

==History==

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 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]] 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 began marketing the drug under the trade name CUBICIN . Cubicin is marketed in the EU and several other countries by [[Novartis]] following its purchase of [[Chiron Corporation]], previous licensee.<ref name=Tally2000>{{cite journal |author=Tally FP, DeBruin MF |title=Development of daptomycin for gram-positive infections |journal=J Antimicrob Chemother. |volume=46 |issue=4 |pages=523–6 |year=2000 |month= October|pmid=11020247 |url=http://jac.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11020247 |doi=10.1093/jac/46.4.523}}</ref><ref name="Charles 2004">{{cite journal |author=Charles PG, Grayson ML |title=The dearth of new antibiotic development: why we should be worried and what we can do about it |journal=Med J Aust. |volume=181 |issue=10 |pages=549–53 |year=2004 |month= November|pmid=15540967 |url=http://www.mja.com.au/public/issues/181_10_151104/cha10412_fm.html}}</ref>

==Mechanism of action==

Daptomycin has a distinct mechanism of action, disrupting multiple aspects of bacterial [[cell membrane]] function. It appears to bind to the membrane and cause rapid [[depolarization]], resulting in a loss of membrane potential leading to inhibition of [[protein]], [[DNA]] and [[RNA]] synthesis, which results in bacterial cell death.

==Microbiology==

Daptomycin is active 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]] and [[Corynebacterium|corynebacteria]].

==Clinical use==

===Indications===

Daptomycin is approved in the United States for [[skin and skin structure infection]]s 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. There seems to be a difference in working daptomycin on hematogenous pneumonia. <ref>{{cite journal

|author=Henken S, Bohling J, et al.

|title=Efficacy Profiles of Daptomycin for Treatment of Invasive and Noninvasive Pulmonary Infections with Streptococcus pneumoniae

|journal=Antimicrob Agents Chemother

|volume=54

|issue=2

|pages=707–717

|year=2010

|month=Feb

|pmid=19917756

|doi=10.1128/AAC.00943-09. }}</ref>

===Efficacy===

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''.<ref>{{cite journal

|author=Fowler VG, Boucher HW, Corey GR

|title=Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus

|journal=N Engl J Med

|volume=355

|issue=7

|pages=653–65

|year=2006

|month=Aug

|pmid=16914701

|doi=10.1056/NEJMoa053783 }}</ref> 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).<ref>{{cite journal

|author=Davis SL, McKinnon PS, Hall LM

|journal=Pharmacotherapy

|year=2007

|volume=27

|issue=12

|pages=1611&ndash;1618

|url=http://www.medscape.com/viewarticle/569439

|pmid=18041881

|doi=10.1592/phco.27.12.1611

|title=Daptomycin versus vancomycin for complicated skin and skin structure infections: clinical and economic outcomes.}}</ref> 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&nbsp;mg/dl, compared to the 10&nbsp;mg/dl or 15&nbsp;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. It is inactivated by pulmonary [[surfactant]]s and is not indicated for the treatment of [[pneumonia]]. Daptomycin has not been studied in patients with [[prosthetic heart valve|prosthetic valve]] endocarditis or [[meningitis]].<ref name=Cubist2005>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</ref>

===Dosage and presentation===

In skin and soft tissue infections, 4&nbsp;mg/kg daptomycin is given intravenously once daily. For ''S. aureus'' bacteraemia or right-sided endocarditis, the approved dose is 6&nbsp;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&nbsp;mg and 350&nbsp;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===

Adverse drug reactions associated with daptomycin therapy include:<ref name="MicromedexDrugdex">Daptomycin. In: Klasco RK, editor. Drugdex system, vol. 129. Greenwood Village (CO): Thomson Micromedex; 2006.</ref>

*Cardiovascular: [[hypotension]] (2.4%), [[hypertension]] (1.1%), [[edema]], cardiac failure, [[supraventricular tachycardia]]

*Central nervous system: headache (5.4%), insomnia (4.5%), dizziness (2.2%), anxiety, confusion, [[Vertigo (medical)|vertigo]], [[paraesthesia]]

*Dermatological: rash (4.3%), [[pruritus]] (2.8%), [[eczema]]

*Endocrine: [[hypokalaemia]], [[hyperglycemia]], [[hypomagnesemia]], increased serum [[bicarbonate]], other [[electrolyte]] disturbances

*Gastrointestinal: constipation (6.2%), nausea (5.8%), diarrhea (5.2%), vomiting (3.2%), dyspepsia (0.9%), abdominal pain, decreased appetite, [[stomatitis]], flatulence

*Hematological: [[anemia]] (2.1%), [[leukocytosis]], [[thrombocytopenia]], [[thrombocytosis]], [[eosinophilia]], increased [[international normalised ratio]] (INR)

*Hepatic: abnormal [[liver function test]]s (3%) (including [[alkaline phosphatase]] and [[lactate dehydrogenase]]), [[jaundice]]

*Musculoskeletal: elevated [[creatine kinase]] (CK) levels (2.8–10.5%), limb pain (1.5%), [[arthralgia]] (0.9%), [[myalgia]], muscle cramps, muscle weakness, [[osteomyelitis]]

*Renal: acute [[renal failure]] (2.2%)

*Respiratory: [[dyspnea]] (2.1%)

*Other: injection site reactions (5.8%), fever (1.9%), [[hypersensitivity]]

There are also reports of [[myopathy]] and [[rhabdomyolysis]] occurring in patients simultaneously taking [[statin]]s<ref>Journal of Antimicrobial Chemotherapy. 63(6):1299-300, 2009 Jun.</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.

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==

[[Image:dap.52.gif|thumb|right|'''Figures 1-7.''' Biosynthesis of Daptomycin]]

[[Image:nbt1265-F2.gif|thumb|right|'''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 |author=Nguyen KT, Kau D, Gu JQ |title=A glutamic acid 3-methyltransferase encoded by an accessory gene locus important for daptomycin biosynthesis in Streptomyces roseosporus |journal=Mol Microbiol. |volume=61 |issue=5 |pages=1294–307 |year=2006 |month= September|pmid=16879412 |doi=10.1111/j.1365-2958.2006.05305.x }}</ref>

[[Image:nbt1265-F2.gif|thumb|right|'''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.

{{essay|date=September 2009}}

Daptomycin is a cyclic lipopeptide antibiotic produced by the organism ''Streptomyces roseosporus''.<ref>{{cite journal |author=Miao V, Coëffet-Legal MF, Brian P |title=Daptomycin biosynthesis in Streptomyces roseosporus: cloning and analysis of the gene cluster and revision of peptide stereochemistry |journal=Microbiology (Reading, Engl.) |volume=151 |issue=Pt 5 |pages=1507–23 |year=2005 |month=May |pmid=15870461 |doi=10.1099/mic.0.27757-0 }}</ref><ref name=Steenbergen>{{cite journal |author=Steenbergen JN, Alder J, Thorne GM, Tally FP |title=Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections |journal=J Antimicrob. Chemother. |volume=55 |issue=3 |pages=283–8 |year=2005 |month= March|pmid=15705644 |doi=10.1093/jac/dkh546 }}</ref> 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.<ref name=Mchenney>{{cite journal |author=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=J Bacteriol. |volume=180 |issue=1 |pages=143–51 |date=1 January 1998|pmid=9422604 |pmc=106860 |url=http://jb.asm.org/cgi/pmidlookup?view=long&pmid=9422604 }}</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 non-proteinogenic 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). 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.<ref name=Fischbach>{{cite journal |author=Fischbach MA, Walsh CT |title=Assembly-line enzymology for polyketide and nonribosomal Peptide antibiotics: logic, machinery, and mechanisms |journal=Chem Rev. |volume=106 |issue=8 |pages=3468–96 |year=2006 |month= August|pmid=16895337 |doi=10.1021/cr0503097 }}</ref> 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.<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.

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).<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 (TE) domain catalyzes chain termination and release of the mature lipopeptide.<ref name=Fischbach/>

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.<ref name=Baltz17160059>{{cite journal |author=Baltz RH |title=Molecular engineering approaches to peptide, polyketide and other antibiotics |journal=Nat Biotechnol. |volume=24 |issue=12 |pages=1533–40 |year=2006 |month= December|pmid=17160059 |doi=10.1038/nbt1265 }}</ref>

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.<ref>{{cite journal |author=Baltz RH |title=Genetic manipulation of antibiotic-producing Streptomyces |journal=Trends Microbiol. |volume=6 |issue=2 |pages=76–83 |year=1998 |month= February|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 |author=Baltz RH, Miao V, Wrigley SK |title=Natural products to drugs: daptomycin and related lipopeptide antibiotics |journal=Nat Prod Rep |volume=22 |issue=6 |pages=717–41 |year=2005 |month= December|pmid=16311632 |doi=10.1039/b416648p }}</ref>

Streptomyces roseosporus, the producer organism of daptomycin, is amenable to genetic manipulation;<ref name=Baltz16193281>{{cite journal |author=Baltz RH, Brian P, Miao V, Wrigley SK |title=Combinatorial biosynthesis of lipopeptide antibiotics in Streptomyces roseosporus |journal=J Ind Microbiol Biotechnol. |volume=33 |issue=2 |pages=66–74 |year=2006 |month= February|pmid=16193281 |doi=10.1007/s10295-005-0030-y }}</ref> the daptomycin biosynthetic gene cluster has been cloned, sequenced and expressed in a 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 |author=Nguyen KT, Ritz D, Gu JQ |title=Combinatorial biosynthesis of novel antibiotics related to daptomycin |journal=Proc Natl Acad Sci USA. |volume=103 |issue=46 |pages=17462–7 |year=2006 |month= November|pmid=17090667 |pmc=1859951 |doi=10.1073/pnas.0608589103 }}</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 |author=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=10474–81 |year=2006 |month= September|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 (CDA) pathways to create molecules containing Trp13, Ile13, or Val13.<ref name=Miao/> 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.<ref name=Nguyen/><ref name=Miao>{{cite journal |author=Miao V, Coëffet-Le Gal MF, Nguyen K |title=Genetic engineering in Streptomyces roseosporus to produce hybrid lipopeptide antibiotics |journal=Chem Biol. |volume=13 |issue=3 |pages=269–76 |year=2006 |month= March|pmid=16638532 |doi=10.1016/j.chembiol.2005.12.012 }}</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&nbsp;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.<ref name=Baltz17160059/>

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 .<ref>{{cite journal |author=Baltz RH |title=Biosynthesis and genetic engineering of lipopeptide antibiotics related to daptomycin |journal=Curr Top Med Chem |volume=8 |issue=8 |pages=618–38 |year=2008 |pmid=18473888 |url=http://www.bentham-direct.org/pages/content.php?CTMC/2008/00000008/00000008/0002R.SGM |doi=10.2174/156802608784221497}}</ref>

==References==

{{Reflist|2}}

==External links==

*{{cite journal | author=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 }}

*{{cite journal | author=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 }}

*{{cite journal |author=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=Clin Infect Dis. |volume=38 |issue=12 |pages=1673–81 |year=2004 |month= June|pmid=15227611 |doi=10.1086/420818 |author6=Daptomycin 98-01 and 99-01 Investigators }}

*[http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=14171 PubChem Substance ID]

*[http://www.whocc.no/atcddd/new_atc_ddd.html New ATC Codes] (from [[WHO]])

* {{UMichOPM|families|superfamily|172}} - Orientations of daptomycin and tsushimycin in membrane

{{Cell wall disruptive antibiotics |Other}}

[[Category:Eli Lilly and Company]]

[[de:Daptomycin]]

[[fr:Daptomycine]]

[[it:Daptomicina]]

[[tr:Daptomisin]]