Drug Information

Drug (ID: DG00066) and It's Reported Resistant Information

• Name: Daptomycin
• Synonyms: Cidecin; Cubicin; Dapcin; Daptomicina; Daptomycine; Daptomycinum; Deptomycin; Daptomicina [Spanish]; Daptomycine [French]; Daptomycinum [Latin]; LY146032; Cubicin (TN); LY-146032; MK-3009; Daptomycin [USAN:INN:BAN]; Daptomycin (JAN/USAN/INN); 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 epsilon1-lactone; N-decanoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanine epsilon(1)-lactone; N-decanoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanine 1.13-3.4-lactone; N-decanoyl-L-tryptophyl-L-asparaginyl-N-[(3S,6S,9R,15S,18R,21S,24S,30S,31R)-3-[2-(2-aminophenyl)-2-oxoethyl]-24-(3-aminopropyl)-15,21-bis(carboxymethyl)-6-[(2R)-1-carboxypropan-2-yl]-9-(hydroxymethyl)-18,31-dimethyl-2,5,8,11,14,17,20,23,26,29-decaoxo-1-ox
• Indication:
  In total 1 Indication(s)
  Bacterial infection [ICD-11: 1A00-1C4Z]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (6 diseases)
  Bacteremia [ICD-11: MA15]; [2], [3], [4]
  Bacterial infection [ICD-11: 1A00-1C4Z]; [5], [6]
  Non-tuberculous mycobacteria infection [ICD-11: 1B21]; [7]
  Right-sided endocarditis [ICD-11: BB41]; [8], [9], [10]
  Staphylococcus meningitis [ICD-11: 1B54]; [11]
  Tissue pyogenic bacterial infection [ICD-11: 1B7Y]; [7]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [1]
• Target: Bacterial Dihydropteroate synthetase (Bact folP); DHPS_ECOLI; [1]
• Formula: C72H101N17O26
• IsoSMILES: CCCCCCCCCC(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H]3[C@H](OC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CNC3=O)CCCN)CC(=O)O)C)CC(=O)O)CO)[C@H](C)CC(=O)O)CC(=O)C4=CC=CC=C4N)C
• InChI: 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
• InChIKey: DOAKLVKFURWEDJ-RWDRXURGSA-N
• PubChem CID: 16134395
• ChEBI ID: CHEBI:600103
• TTD Drug ID: D05HPI
• INTEDE ID: DR2142
• DrugBank ID: DB00080

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Bacterial infection [ICD-11: 1A00-1C4Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Sensor protein kinase WalK (WALK) [5], [6]

• Molecule Alteration: Missense mutation; p.S221P
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Staphylococcus aureus MW2; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1616; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1617; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1618; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CiproR; 1242971
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The exact mechanism by which the changes in YycG alter the protein's function is not known. Martin et al. suggested that yycF and yycG are involved in cell permeability and showed that loss of yycF activity results in increased susceptibility to macrolide and lincosamide antibiotics and unsaturated long-chain fatty acids.

Key Molecule: Sensor protein kinase WalK (WALK) [5], [6]

• Molecule Alteration: Missense mutation; p.R263C
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Staphylococcus aureus MW2; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1616; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1617; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1618; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CiproR; 1242971
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The exact mechanism by which the changes in YycG alter the protein's function is not known. Martin et al. suggested that yycF and yycG are involved in cell permeability and showed that loss of yycF activity results in increased susceptibility to macrolide and lincosamide antibiotics and unsaturated long-chain fatty acids.

Key Molecule: Sensor protein kinase WalK (WALK) [5], [6]

• Molecule Alteration: Missense mutation; c.26121insA
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Staphylococcus aureus MW2; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1616; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1617; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CB1618; 1242971
• In Vitro Model: Staphylococcus aureus MW2-CiproR; 1242971
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The exact mechanism by which the changes in YycG alter the protein's function is not known. Martin et al. suggested that yycF and yycG are involved in cell permeability and showed that loss of yycF activity results in increased susceptibility to macrolide and lincosamide antibiotics and unsaturated long-chain fatty acids.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione biosynthesis bifunctional protein GshAB (GSHAB ) [12]

• Molecule Alteration: Missense mutation; p.E354K
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis S613; 699185
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: As a glutathione synthase, GshF has previously been implicated in the oxidative stress response across multiple species. GshF is commonly found among mammalian pathogens and could have a role in mitigating DNA damage caused by general oxidative. stress.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Transcriptional regulatory protein LiaR (LIAR) [12]

• Molecule Alteration: Missense mutation; p.D191N
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis S613; 699185
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: LiaFSR is a component of the CESR regulon and responds to changes in cell envelope integrity by regulating downstream genes to counteract damage.LiaFSR mutations occurred in liaF (78%), with changes in yvlB (12%) and liaR (4%) comprising the remainder.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette transporter A (ABCA) [2], [3], [4]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Staphylococcus aureus MW2; 1242971
• In Vivo Model: Swiss webster male mice model; Mus musculus
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The ATP-dependent transporter gene abcA in Staphylococcus aureus confers resistance to hydrophobic Beta-lactams.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatidate cytidylyltransferase (CDSA) [1]

• Molecule Alteration: Missense mutation; p.D222N
• Resistant Disease: Streptococcus mitis/oralis infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Streptococcus mitis isolates; 28037
• In Vitro Model: Streptococcus oralis isolates; 1303
• Experiment for Molecule Alteration: PCR; DNA sequence assay
• Mechanism Description: Mutation changes in CdsA cause daptomycin resistance in S. mitis/oralis.

Key Molecule: Cardiolipin synthase (CLS) [10], [12], [13]

• Molecule Alteration: Missense mutation; p.R218Q
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis S613; 699185
• In Vitro Model: Enterococcus faecium S447; 1134840
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Mol00855
• Mechanism Description: Mutations in genes encoding proteins associated with cell envelope homeostasis (yycFG and liaFSR) and phospholipid metabolism (cardiolipin synthase [cls] and cyclopropane fatty acid synthetase [cfa]) were investigated in daptomycin resistance derivatives.

Key Molecule: Cardiolipin synthase (CLS) [10], [12], [13]

• Molecule Alteration: Missense mutation; p.R267H
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis S613; 699185
• In Vitro Model: Enterococcus faecium S447; 1134840
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Mol00855
• Mechanism Description: Mutations in genes encoding proteins associated with cell envelope homeostasis (yycFG and liaFSR) and phospholipid metabolism (cardiolipin synthase [cls] and cyclopropane fatty acid synthetase [cfa]) were investigated in daptomycin resistance derivatives.

Key Molecule: Cardiolipin synthase (CLS) [10], [12], [13]

• Molecule Alteration: Frameshift mutation; p.NFQ77-79del
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis S613; 699185
• In Vitro Model: Enterococcus faecium S447; 1134840
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Mol00855
• Mechanism Description: Mutations in genes encoding proteins associated with cell envelope homeostasis (yycFG and liaFSR) and phospholipid metabolism (cardiolipin synthase [cls] and cyclopropane fatty acid synthetase [cfa]) were investigated in daptomycin resistance derivatives.

Non-tuberculous mycobacteria infection [ICD-11: 1B21]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cardiolipin synthase 2 (CLS2) [7]

• Molecule Alteration: Missense mutation; p.A23V+p.T33N+p.L52F+p.F60S
• Resistant Disease: Complicated skin infection Staphylococcus aureus infection [ICD-11: 1B21.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Staphylococcus aureus MRSA32 [A5948]; 553567
• In Vitro Model: Staphylococcus aureus RN6607 [A8115]; 553573
• In Vitro Model: Staphylococcus aureus RN9120 [A8117]; 553574
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Mutation in each of these genes act similarly to reduce the net-negative charge of the cell membrane leading to electrorepulsion of daptomycin. They may act in isolation or in concert with each other, particularly for mutations in mprF and cls2.

Key Molecule: Phosphatidylglycerophosphate synthase (PGSA) [7]

• Molecule Alteration: Missense mutation; p.V59D+p.A64V+p.K75N+p.Ins.G76;Q77+p.S177F
• Resistant Disease: Complicated skin infection Staphylococcus aureus infection [ICD-11: 1B21.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Staphylococcus aureus MRSA32 [A5948]; 553567
• In Vitro Model: Staphylococcus aureus RN6607 [A8115]; 553573
• In Vitro Model: Staphylococcus aureus RN9120 [A8117]; 553574
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Mutation in each of these genes act similarly to reduce the net-negative charge of the cell membrane leading to electrorepulsion of daptomycin. They may act in isolation or in concert with each other, particularly for mutations in mprF and cls2.

Staphylococcus meningitis [ICD-11: 1B54]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cardiolipin synthase 2 (CLS2) [7]

• Molecule Alteration: Missense mutation; p.A23V+p.T33N+p.L52F+p.F60S
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Staphylococcus aureus MRSA32 [A5948]; 553567
• In Vitro Model: Staphylococcus aureus RN6607 [A8115]; 553573
• In Vitro Model: Staphylococcus aureus RN9120 [A8117]; 553574
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Mutation in each of these genes act similarly to reduce the net-negative charge of the cell membrane leading to electrorepulsion of daptomycin. They may act in isolation or in concert with each other, particularly for mutations in mprF and cls2.

Key Molecule: Phosphatidylglycerophosphate synthase (PGSA) [7]

• Molecule Alteration: Missense mutation; p.V59D+p.A64V+p.K75N+p.Ins.G76;Q77+p.S177F
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Staphylococcus aureus MRSA32 [A5948]; 553567
• In Vitro Model: Staphylococcus aureus RN6607 [A8115]; 553573
• In Vitro Model: Staphylococcus aureus RN9120 [A8117]; 553574
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Mutation in each of these genes act similarly to reduce the net-negative charge of the cell membrane leading to electrorepulsion of daptomycin. They may act in isolation or in concert with each other, particularly for mutations in mprF and cls2.

Key Molecule: Phosphatidylglycerol lysyltransferase (MPREF) [11]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21(DE3); 469008
• Experiment for Molecule Alteration: TLC and Western blotting analysis
• Experiment for Drug Resistance: Epsilometer test (E test) assay
• Mechanism Description: MprF does not only synthesize Lys-PG but also accomplishes translocation of Lys-PG from the inner to the outer surface of the membrane. Lys-PG mediates CAMP resistance by repulsing the cationic peptides from the outer surface of the membrane.

Tissue pyogenic bacterial infection [ICD-11: 1B7Y]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cardiolipin synthase 2 (CLS2) [7]

• Molecule Alteration: Missense mutation; p.A23V+p.T33N+p.L52F+p.F60S
• Resistant Disease: Complicated soft tissue infection [ICD-11: 1B7Y.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Staphylococcus aureus MRSA32 [A5948]; 553567
• In Vitro Model: Staphylococcus aureus RN6607 [A8115]; 553573
• In Vitro Model: Staphylococcus aureus RN9120 [A8117]; 553574
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Mutation in each of these genes act similarly to reduce the net-negative charge of the cell membrane leading to electrorepulsion of daptomycin. They may act in isolation or in concert with each other, particularly for mutations in mprF and cls2.

Key Molecule: Phosphatidylglycerophosphate synthase (PGSA) [7]

• Molecule Alteration: Missense mutation; p.V59D+p.A64V+p.K75N+p.Ins.G76;Q77+p.S177F
• Resistant Disease: Complicated soft tissue infection [ICD-11: 1B7Y.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Staphylococcus aureus MRSA32 [A5948]; 553567
• In Vitro Model: Staphylococcus aureus RN6607 [A8115]; 553573
• In Vitro Model: Staphylococcus aureus RN9120 [A8117]; 553574
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Mutation in each of these genes act similarly to reduce the net-negative charge of the cell membrane leading to electrorepulsion of daptomycin. They may act in isolation or in concert with each other, particularly for mutations in mprF and cls2.

ICD-11: Circulatory system diseases

Right-sided endocarditis [ICD-11: BB41]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cardiolipin synthase (CLS) [8], [9], [10]

• Molecule Alteration: Missense mutation; p.R218Q
• Resistant Disease: Right-sided endocarditis [ICD-11: BB41.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis S613; 699185
• In Vitro Model: Enterococcus faecium S447; 1134840
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Daptomycin (DAP) resistance in enterococci has been linked to mutations in genes that alter the cell envelope stress response (CESR) (liaFSR) and changes in enzymes that directly affect phospholipid homeostasis, and these changes may alter membrane composition, such as that of cardiolipin synthase (Cls).A comparison of the catalytic activities of E. faecium Cls447a to those of Cls447aH215R and Cls447aR218Q shows that mutations associated with DAP resistance increase Cls activity.

Key Molecule: Cardiolipin synthase 2 (CLS2) [7]

• Molecule Alteration: Missense mutation; p.A23V+p.T33N+p.L52F+p.F60S
• Resistant Disease: Right-sided endocarditis [ICD-11: BB41.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Staphylococcus aureus MRSA32 [A5948]; 553567
• In Vitro Model: Staphylococcus aureus RN6607 [A8115]; 553573
• In Vitro Model: Staphylococcus aureus RN9120 [A8117]; 553574
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Mutation in each of these genes act similarly to reduce the net-negative charge of the cell membrane leading to electrorepulsion of daptomycin. They may act in isolation or in concert with each other, particularly for mutations in mprF and cls2.

Key Molecule: Phosphatidylglycerophosphate synthase (PGSA) [7]

• Molecule Alteration: Missense mutation; p.V59D+p.A64V+p.K75N+p.Ins.G76;Q77+p.S177F
• Resistant Disease: Right-sided endocarditis [ICD-11: BB41.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Staphylococcus aureus MRSA32 [A5948]; 553567
• In Vitro Model: Staphylococcus aureus RN6607 [A8115]; 553573
• In Vitro Model: Staphylococcus aureus RN9120 [A8117]; 553574
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Mutation in each of these genes act similarly to reduce the net-negative charge of the cell membrane leading to electrorepulsion of daptomycin. They may act in isolation or in concert with each other, particularly for mutations in mprF and cls2.

ICD-21: Symptoms/clinical signs/unclassified clinical findings

Bacteremia [ICD-11: MA15]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette transporter A (ABCA) [2], [3], [4]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bacteremia [ICD-11: MA15.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Staphylococcus aureus MW2; 1242971
• In Vivo Model: Swiss webster male mice model; Mus musculus
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The ATP-dependent transporter gene abcA in Staphylococcus aureus confers resistance to hydrophobic Beta-lactams.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cardiolipin synthase (CLS) [8], [9], [10]

• Molecule Alteration: Missense mutation; p.H215R
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis S613; 699185
• In Vitro Model: Enterococcus faecium S447; 1134840
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: Daptomycin (DAP) resistance in enterococci has been linked to mutations in genes that alter the cell envelope stress response (CESR) (liaFSR) and changes in enzymes that directly affect phospholipid homeostasis, and these changes may alter membrane composition, such as that of cardiolipin synthase (Cls).A comparison of the catalytic activities of E. faecium Cls447a to those of Cls447aH215R and Cls447aR218Q shows that mutations associated with DAP resistance increase Cls activity.

Key Molecule: Cardiolipin synthase 2 (CLS2) [7]

• Molecule Alteration: Missense mutation; p.A23V+p.T33N+p.L52F+p.F60S
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Staphylococcus aureus MRSA32 [A5948]; 553567
• In Vitro Model: Staphylococcus aureus RN6607 [A8115]; 553573
• In Vitro Model: Staphylococcus aureus RN9120 [A8117]; 553574
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Mutation in each of these genes act similarly to reduce the net-negative charge of the cell membrane leading to electrorepulsion of daptomycin. They may act in isolation or in concert with each other, particularly for mutations in mprF and cls2.

Key Molecule: Phosphatidylglycerophosphate synthase (PGSA) [7]

• Molecule Alteration: Missense mutation; p.V59D+p.A64V+p.K75N+p.Ins.G76;Q77+p.S177F
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus isolates; 1280
• In Vitro Model: Staphylococcus aureus MRSA32 [A5948]; 553567
• In Vitro Model: Staphylococcus aureus RN6607 [A8115]; 553573
• In Vitro Model: Staphylococcus aureus RN9120 [A8117]; 553574
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Mutation in each of these genes act similarly to reduce the net-negative charge of the cell membrane leading to electrorepulsion of daptomycin. They may act in isolation or in concert with each other, particularly for mutations in mprF and cls2.

Key Molecule: DUF2154 domain-containing protein (LIAF) [8]

• Molecule Alteration: Frameshift mutation; p.170Idel
• Resistant Disease: Bacteremia [ICD-11: MA15.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis S613; 699185
• In Vitro Model: Enterococcus faecalis R712; 699186
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The daptomycin-resistant isolate - had changes in the structure of the cell envelope and alterations in membrane permeability and membrane potential.

Key Molecule: DUF2154 domain-containing protein/Glycerophosphoryl diester phosphodiesterase family protein (LIAF/GDPD) [8]

• Molecule Alteration: Frameshift mutation; liaF p.170Idel +gdpD p.177ldel
• Resistant Disease: Bacteremia [ICD-11: MA15.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Enterococcus faecalis S613; 699185
• In Vitro Model: Enterococcus faecalis R712; 699186
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: The daptomycin-resistant isolate - had changes in the structure of the cell envelope and alterations in membrane permeability and membrane potential.

References

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