Drug Information

Drug (ID: DG00380) and It's Reported Resistant Information
Name
Bacitracin F
Synonyms
Bacitracin F; 5-[[1-[[3-(2-amino-2-oxoethyl)-18-(3-aminopropyl)-12-benzyl-15-butan-2-yl-6-(carboxymethyl)-9-(1H-imidazol-5-ylmethyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclopentacos-21-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-4-[[4-methyl-2-[[2-(2-methylbutanoyl)-1,3-thiazole-4-carbonyl]amino]pentanoyl]amino]-5-oxopentanoic acid; 22601-63-4; UNII-W7FFC6JWF9; W7FFC6JWF9; Bacitracin F (~75per cent); B021
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Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
Bacterial infection [ICD-11: 1A00-1C4Z]
[1]
Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (3 diseases)
Bacillus infection [ICD-11: 1C4Y]
[2]
Escherichia coli intestinal infection [ICD-11: 1A03]
[2]
Sepsis [ICD-11: 1G40]
[3]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C66H98N16O17S
IsoSMILES
CCC(C)C1C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NCCCCC(C(=O)NC(C(=O)N1)CCCN)NC(=O)C(C(C)CC)NC(=O)C(CCC(=O)O)NC(=O)C(CC(C)C)NC(=O)C2=CSC(=N2)C(=O)C(C)CC)CC(=O)N)CC(=O)O)CC3=CN=CN3)CC4=CC=CC=C4
InChI
1S/C66H98N16O17S/c1-9-35(6)52(82-58(92)42(22-23-50(84)85)73-59(93)43(26-34(4)5)75-63(97)48-32-100-66(80-48)54(88)37(8)11-3)64(98)74-40-20-15-16-25-70-55(89)46(29-49(68)83)77-62(96)47(30-51(86)87)78-61(95)45(28-39-31-69-33-71-39)76-60(94)44(27-38-18-13-12-14-19-38)79-65(99)53(36(7)10-2)81-57(91)41(21-17-24-67)72-56(40)90/h12-14,18-19,31-37,40-47,52-53H,9-11,15-17,20-30,67H2,1-8H3,(H2,68,83)(H,69,71)(H,70,89)(H,72,90)(H,73,93)(H,74,98)(H,75,97)(H,76,94)(H,77,96)(H,78,95)(H,79,99)(H,81,91)(H,82,92)(H,84,85)(H,86,87)
InChIKey
FCLQHQCOKGKLHR-UHFFFAOYSA-N
PubChem CID
3082210
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
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Bacterial infection [ICD-11: 1A00-1C4Z]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Undecaprenyl-diphosphatase (UPPP) [1]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Bacterial infection [ICD-11: 1A00-1C4Z]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model Escherichia coli DH10B 316385
Enterococcus faecalis JH2-2 1351
Enterococcus faecalis V583 226185
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]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Bacitracin transport permease protein BCRB (BCRB) [2]
Molecule Alteration Expression
Acquired
 Molecule Info 
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
 Disease Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli strain HB101 634468
Escherichia coli strain DH5alpha 668369
Bacillus subtilis strain 1A685 1423
Bacillus subtilis strain vectors pHV143 1423
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) [2]
Molecule Alteration Expression
Acquired
 Molecule Info 
Resistant Disease Escherichia coli infection [ICD-11: 1A03.0]
 Disease Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli strain HB101 634468
Escherichia coli strain DH5alpha 668369
Bacillus subtilis strain 1A685 1423
Bacillus subtilis strain vectors pHV143 1423
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]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Bacitracin transport permease protein BCRB (BCRB) [2]
Molecule Alteration Expression
Inherence
 Molecule Info 
Resistant Disease Bacillus licheniformis infection [ICD-11: 1C4Y.2]
 Disease Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli strain HB101 634468
Escherichia coli strain DH5alpha 668369
Bacillus subtilis strain 1A685 1423
Bacillus subtilis strain vectors pHV143 1423
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) [2]
Molecule Alteration Expression
Inherence
 Molecule Info 
Resistant Disease Bacillus licheniformis infection [ICD-11: 1C4Y.2]
 Disease Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli strain HB101 634468
Escherichia coli strain DH5alpha 668369
Bacillus subtilis strain 1A685 1423
Bacillus subtilis strain vectors pHV143 1423
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]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Undecaprenyl-diphosphatase BcrC (BCRC) [3]
Molecule Alteration Expression
Inherence
 Molecule Info 
Resistant Disease Bacillus subtilis infection [ICD-11: 1G40.1]
 Disease Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli C41(DE3) 469008
Escherichia coli DH5alpha 668369
Bacillus subtilis 168 224308
Bacillus subtilis BFS82 1423
Bacillus subtilis BSmrs168 1423
Bacillus subtilis BSmrs173 1423
Bacillus subtilis BSmrs175 1423
Bacillus subtilis BSmrs194 1423
Bacillus subtilis BSmrs201 1423
Escherichia coli Ecmrs144 562
Escherichia coli Ecmrs150 562
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) Click to Show/Hide
Key Molecule: Bacitracin transport permease protein BCRB (BCRB) [2]
Molecule Alteration Expression
Acquired
 Molecule Info 
Resistant Disease Bacillus subtilis infection [ICD-11: 1G40.1]
 Disease Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli strain HB101 634468
Escherichia coli strain DH5alpha 668369
Bacillus subtilis strain 1A685 1423
Bacillus subtilis strain vectors pHV143 1423
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) [2]
Molecule Alteration Expression
Acquired
 Molecule Info 
Resistant Disease Bacillus subtilis infection [ICD-11: 1G40.1]
 Disease Info 
Experimental Note Discovered Using In-vivo Testing Model
In Vitro Model Escherichia coli strain HB101 634468
Escherichia coli strain DH5alpha 668369
Bacillus subtilis strain 1A685 1423
Bacillus subtilis strain vectors pHV143 1423
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 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 3 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.

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