Disease Information

General Information of the Disease (ID: DIS00121)

• Name: Right-sided endocarditis
• ICD: ICD-11: BB41

Type(s) of Resistant Mechanism of This Disease

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Daptomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cardiolipin synthase (CLS) [1], [2], [3]

• Resistant Disease: Right-sided endocarditis [ICD-11: BB41.0]
• Molecule Alteration: Missense mutation; p.R218Q
• Resistant Drug: Daptomycin
• 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) [4]

• Resistant Disease: Right-sided endocarditis [ICD-11: BB41.0]
• Molecule Alteration: Missense mutation; p.A23V+p.T33N+p.L52F+p.F60S
• Resistant Drug: Daptomycin
• 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) [4]

• Resistant Disease: Right-sided endocarditis [ICD-11: BB41.0]
• Molecule Alteration: Missense mutation; p.V59D+p.A64V+p.K75N+p.Ins.G76;Q77+p.S177F
• Resistant Drug: Daptomycin
• 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.

References

• Ref 1: Genetic basis for in vivo daptomycin resistance in enterococci. N Engl J Med. 2011 Sep 8;365(10):892-900. doi: 10.1056/NEJMoa1011138.
• Ref 2: Genotypic and phenotypic evaluation of the evolution of high-level daptomycin nonsusceptibility in vancomycin-resistant Enterococcus faecium. Antimicrob Agents Chemother. 2012 Nov;56(11):6051-3. doi: 10.1128/AAC.01318-12. Epub 2012 Sep 4.
• Ref 3: Biochemical characterization of cardiolipin synthase mutations associated with daptomycin resistance in enterococci. Antimicrob Agents Chemother. 2013 Jan;57(1):289-96. doi: 10.1128/AAC.01743-12. Epub 2012 Oct 31.
• Ref 4: Whole genome characterization of the mechanisms of daptomycin resistance in clinical and laboratory derived isolates of Staphylococcus aureus. PLoS One. 2012;7(1):e28316. doi: 10.1371/journal.pone.0028316. Epub 2012 Jan 6.