Drug Information

Drug (ID: DG00479) and It's Reported Resistant Information

• Name: Bacitracin methylene disalicylate
• Synonyms: Bacitracin methylene disalicylate; Bacitracin methylene disalicylate; 55852-84-1; MD bacitracin; Kemitracin 10; Caswell No. 066D; Fortracin (bacitracin-MD); Bacitracin, methylenebis(2-hydroxybenzoate); Bacitracin methylenedisalicylate; Bacitracin methylenedisalicylic acid; EINECS 259-862-3; Methylenebis(2-hydroxybenzoate)bacitracin; Bacitracin, methylenebis(2-hydroxybenzoate) (salt)
• 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 (2 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [1]
  COVID-19 [ICD-11: 1D92]; [2]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (3 diseases)
  Bacillus infection [ICD-11: 1C4Y]; [3]
  Escherichia coli intestinal infection [ICD-11: 1A03]; [3]
  Sepsis [ICD-11: 1G40]; [4]
• Formula: C81H117N17O23S
• IsoSMILES: CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC2=CN=CN2)C(=O)N[C@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@@H](CCC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)C3CSC(=N3)C(C(C)CC)N.C1=CC=C(C(=C1)C(=O)OCOC(=O)C2=CC=CC=C2O)O
• InChI: 1S/C66H105N17O17S.C15H12O6/c1-9-35(6)52(70)65-81-48(32-101-65)62(96)76-43(26-34(4)5)58(92)74-42(22-23-50(85)86)57(91)83-53(36(7)10-2)63(97)75-40(20-15-16-24-67)55(89)73-41(21-17-25-68)56(90)82-54(37(8)11-3)64(98)79-44(27-38-18-13-12-14-19-38)59(93)77-45(28-39-31-71-33-72-39)60(94)78-46(30-51(87)88)61(95)80-47(66(99)100)29-49(69)84;16-12-7-3-1-5-10(12)14(18)20-9-21-15(19)11-6-2-4-8-13(11)17/h12-14,18-19,31,33-37,40-48,52-54H,9-11,15-17,20-30,32,67-68,70H2,1-8H3,(H2,69,84)(H,71,72)(H,73,89)(H,74,92)(H,75,97)(H,76,96)(H,77,93)(H,78,94)(H,79,98)(H,80,95)(H,82,90)(H,83,91)(H,85,86)(H,87,88)(H,99,100);1-8,16-17H,9H2/t35 ,36-,37-,40-,41+,42+,43-,44+,45-,46+,47-,48 ,52 ,53-,54-;/m0./s1
• PubChem CID: 11980094
• DrugBank ID: DB00626

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  IDUE: Irregularity in Drug Uptake and Drug Efflux

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: Undecaprenyl-diphosphatase (UPPP) [1]

• 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 DH10B; 316385
• In Vitro Model: Enterococcus faecalis JH2-2; 1351
• In Vitro Model: Enterococcus faecalis V583; 226185
• In Vitro Model: Escherichia coli MC1061; 1211845
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Binding of bacitracin to UPP prevents its dephosphorylation, thereby disrupting the regeneration of UP.Depletion of the available carrier lipids leads to the inhibition of the cell wall synthesis, resulting eventually in cell death.Low-level bacitracin resistance in E. faecalis is mediated by a BacA-type UppP.

Escherichia coli intestinal infection [ICD-11: 1A03]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bacitracin transport permease protein BCRB (BCRB) [3]

• Molecule Alteration: Expression; Acquired
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Escherichia coli strain DH5alpha; 668369
• In Vitro Model: Bacillus subtilis strain 1A685; 1423
• In Vitro Model: Bacillus subtilis strain vectors pHV143; 1423
• In Vitro Model: Bacillus ticheniformis strain FD; 1402
• Experiment for Molecule Alteration: Dideoxynucleotide chain-termination method assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The nucleotide sequence of the Bacillus licheniformis bacitracin-resistance locus was determined. The presence of three open reading frames, bcrA, bcrB and bcrC, was revealed. The BcrA protein shares a high degree of homology with the hydrophilic ATP-binding components of the ABC family of transport proteins. The bcrB and bcrC genes were found to encode hydrophobic proteins, which may function as membrane components of the permease. Apart from Bacillus subtilis, these genes also confer resistance upon the Gram-negative Escherichia coli.

Key Molecule: Bacitracin transport ATP-binding protein BcrA (BCRA) [3]

• Molecule Alteration: Expression; Acquired
• Resistant Disease: Escherichia coli infection [ICD-11: 1A03.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Escherichia coli strain DH5alpha; 668369
• In Vitro Model: Bacillus subtilis strain 1A685; 1423
• In Vitro Model: Bacillus subtilis strain vectors pHV143; 1423
• In Vitro Model: Bacillus ticheniformis strain FD; 1402
• Experiment for Molecule Alteration: Dideoxynucleotide chain-termination method assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The nucleotide sequence of the Bacillus licheniformis bacitracin-resistance locus was determined. The presence of three open reading frames, bcrA, bcrB and bcrC, was revealed. The BcrA protein shares a high degree of homology with the hydrophilic ATP-binding components of the ABC family of transport proteins. The bcrB and bcrC genes were found to encode hydrophobic proteins, which may function as membrane components of the permease. Apart from Bacillus subtilis, these genes also confer resistance upon the Gram-negative Escherichia coli.

Bacillus infection [ICD-11: 1C4Y]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bacitracin transport permease protein BCRB (BCRB) [3]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Bacillus licheniformis infection [ICD-11: 1C4Y.2]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Escherichia coli strain DH5alpha; 668369
• In Vitro Model: Bacillus subtilis strain 1A685; 1423
• In Vitro Model: Bacillus subtilis strain vectors pHV143; 1423
• In Vitro Model: Bacillus ticheniformis strain FD; 1402
• Experiment for Molecule Alteration: Dideoxynucleotide chain-termination method assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: How could the proposed export function of the Bcr permease account for the bacitracin resistance The transported molecule could be either the substance inactivating the antibiotic or the antibiotic alone. As already observed. some of the metabolites could inhibit the bactericidal activity of bacitracin at very low concentrations. However, in S. subfitis and Escherichia coli strains carrying cloned bcr genes, no substances that could suppress bacitracin activity were detected. It seems that the bacitracin is indeed the target of the Bcr ABC transporter.

Key Molecule: Bacitracin transport ATP-binding protein BcrA (BCRA) [3]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Bacillus licheniformis infection [ICD-11: 1C4Y.2]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Escherichia coli strain DH5alpha; 668369
• In Vitro Model: Bacillus subtilis strain 1A685; 1423
• In Vitro Model: Bacillus subtilis strain vectors pHV143; 1423
• In Vitro Model: Bacillus ticheniformis strain FD; 1402
• Experiment for Molecule Alteration: Dideoxynucleotide chain-termination method assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: How could the proposed export function of the Bcr permease account for the bacitracin resistance The transported molecule could be either the substance inactivating the antibiotic or the antibiotic alone. As already observed. some of the metabolites could inhibit the bactericidal activity of bacitracin at very low concentrations. However, in S. subfitis and Escherichia coli strains carrying cloned bcr genes, no substances that could suppress bacitracin activity were detected. It seems that the bacitracin is indeed the target of the Bcr ABC transporter.

Sepsis [ICD-11: 1G40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Undecaprenyl-diphosphatase BcrC (BCRC) [4]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Bacillus subtilis infection [ICD-11: 1G40.1]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli C41(DE3); 469008
• In Vitro Model: Escherichia coli DH5alpha; 668369
• In Vitro Model: Bacillus subtilis 168; 224308
• In Vitro Model: Bacillus subtilis BFS82; 1423
• In Vitro Model: Bacillus subtilis BSmrs168; 1423
• In Vitro Model: Bacillus subtilis BSmrs173; 1423
• In Vitro Model: Bacillus subtilis BSmrs175; 1423
• In Vitro Model: Bacillus subtilis BSmrs194; 1423
• In Vitro Model: Bacillus subtilis BSmrs201; 1423
• In Vitro Model: Escherichia coli Ecmrs144; 562
• In Vitro Model: Escherichia coli Ecmrs150; 562
• In Vitro Model: Escherichia coli Ecmrs151; 562
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: Microtiter tray assay
• Mechanism Description: Overexpression of the BcrCBs protein, formerly called YwoA, in Escherichia coli or in Bacillus subtilis allows these bacteria to stand higher concentrations of bacitracin.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Bacitracin transport permease protein BCRB (BCRB) [3]

• Molecule Alteration: Expression; Acquired
• Resistant Disease: Bacillus subtilis infection [ICD-11: 1G40.1]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Escherichia coli strain DH5alpha; 668369
• In Vitro Model: Bacillus subtilis strain 1A685; 1423
• In Vitro Model: Bacillus subtilis strain vectors pHV143; 1423
• In Vitro Model: Bacillus ticheniformis strain FD; 1402
• Experiment for Molecule Alteration: Dideoxynucleotide chain-termination method assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The nucleotide sequence of the Bacillus licheniformis bacitracin-resistance locus was determined. The presence of three open reading frames, bcrA, bcrB and bcrC, was revealed. The BcrA protein shares a high degree of homology with the hydrophilic ATP-binding components of the ABC family of transport proteins. The bcrB and bcrC genes were found to encode hydrophobic proteins, which may function as membrane components of the permease. Apart from Bacillus subtilis, these genes also confer resistance upon the Gram-negative Escherichia coli.

Key Molecule: Bacitracin transport ATP-binding protein BcrA (BCRA) [3]

• Molecule Alteration: Expression; Acquired
• Resistant Disease: Bacillus subtilis infection [ICD-11: 1G40.1]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain HB101; 634468
• In Vitro Model: Escherichia coli strain DH5alpha; 668369
• In Vitro Model: Bacillus subtilis strain 1A685; 1423
• In Vitro Model: Bacillus subtilis strain vectors pHV143; 1423
• In Vitro Model: Bacillus ticheniformis strain FD; 1402
• Experiment for Molecule Alteration: Dideoxynucleotide chain-termination method assay
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: The nucleotide sequence of the Bacillus licheniformis bacitracin-resistance locus was determined. The presence of three open reading frames, bcrA, bcrB and bcrC, was revealed. The BcrA protein shares a high degree of homology with the hydrophilic ATP-binding components of the ABC family of transport proteins. The bcrB and bcrC genes were found to encode hydrophobic proteins, which may function as membrane components of the permease. Apart from Bacillus subtilis, these genes also confer resistance upon the Gram-negative Escherichia coli.

References

• Ref 1: Undecaprenyl pyrophosphate phosphatase confers low-level resistance to bacitracin in Enterococcus faecalis. J Antimicrob Chemother. 2013 Jul;68(7):1583-93. doi: 10.1093/jac/dkt048. Epub 2013 Mar 3.
• Ref 2: Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7 Nature. 2021 May;593(7857):130-135. doi: 10.1038/s41586-021-03398-2. Epub 2021 Mar 8.
• Ref 3: Bacillus licheniformis bacitracin-resistance ABC transporter: relationship to mammalian multidrug resistance. Mol Microbiol. 1995 Jun;16(5):969-76. doi: 10.1111/j.1365-2958.1995.tb02322.x.
• Ref 4: BcrC from Bacillus subtilis acts as an undecaprenyl pyrophosphate phosphatase in bacitracin resistance. J Biol Chem. 2005 Aug 12;280(32):28852-7. doi: 10.1074/jbc.M413750200. Epub 2005 Jun 9.