Drug Information

Drug (ID: DG00291) and It's Reported Resistant Information

• Name: Coumermycin
• Indication:
  In total 1 Indication(s)
  Discovery agent [ICD-11: N.A.]; Investigative; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (2 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [2]
  Bartonellosis [ICD-11: 1C11]; [1]
• Target: Bacterial DNA gyrase B (Bact gyrB); GYRB_ECOLI; [1]
• Formula: C55H59N5O20
• IsoSMILES: CC1=CC=C(N1)C(=O)O[C@H]2[C@H]([C@@H](OC([C@@H]2OC)(C)C)OC3=C(C4=C(C=C3)C(=C(C(=O)O4)NC(=O)C5=CNC(=C5C)C(=O)NC6=C(C7=C(C(=C(C=C7)O[C@H]8[C@@H]([C@@H]([C@H](C(O8)(C)C)OC)OC(=O)C9=CC=C(N9)C)O)C)OC6=O)O)O)C)O
• InChI: 1S/C55H59N5O20/c1-21-12-16-29(57-21)48(67)77-42-38(63)52(79-54(6,7)44(42)71-10)73-31-18-14-26-36(61)34(50(69)75-40(26)24(31)4)59-46(65)28-20-56-33(23(28)3)47(66)60-35-37(62)27-15-19-32(25(5)41(27)76-51(35)70)74-53-39(64)43(45(72-11)55(8,9)80-53)78-49(68)30-17-13-22(2)58-30/h12-20,38-39,42-45,52-53,56-58,61-64H,1-11H3,(H,59,65)(H,60,66)/t38-,39-,42+,43+,44-,45-,52-,53-/m1/s1
• InChIKey: WTIJXIZOODAMJT-DHFGXMAYSA-N
• PubChem CID: 54675768
• ChEBI ID: CHEBI:3907
• TTD Drug ID: D0X3FT
• DrugBank ID: DB13912

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

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: DNA gyrase subunit B (GYRB) [2]

• Molecule Alteration: Missense mutation; p.R136C+p.R136H+p.R136S+p.G164V
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Escherichia coli JM109; 562
• In Vitro Model: Escherichia coli strain N4177; 562
• In Vitro Model: Escherichia coli strain CC1; 562
• In Vitro Model: Escherichia coli strain CC5; 562
• In Vitro Model: Escherichia coli strain LE234; 562
• In Vitro Model: Escherichia coli strain LE316; 562
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Broth microdilution method assay
• Mechanism Description: Coumarins are inhibitors of the ATP hydrolysis and DNA supercoiling reactions catalysed by DNA gyrase. four mutations have been identified regaeding conferring coumarin resistance to Escherichia coli: Arg-136 to Cys, His or Ser and Gly-164 to Val.Significant differences in the susceptibility of mutant GyrB proteins to inhibition by either chlorobiocin and novobiocin or coumermycin have been found, suggesting wider contacts between coumermycin and GyrB.

Bartonellosis [ICD-11: 1C11]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [1]

• Molecule Alteration: Missense mutation; p.G124S
• Resistant Disease: Bartonella bacilliformis infection [ICD-11: 1C11.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Bartonella bacilliformis kC583; 360095
• In Vitro Model: Bartonella bacilliformis strain CR1-CR12; 774
• In Vitro Model: Escherichia coli strain N4177; 562
• In Vitro Model: Escherichia coli strain N99; 562
• In Vitro Model: Escherichia coli strain TOP10F'; 562
• Experiment for Molecule Alteration: DNA hybridizations assay
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: First, in 5 of the 12 coumermycin A1-resistant strains (CR1, CR2, CR6, CR8, and CR9), identical G-to-A transitions at base 370 of the 2,079-bp ORF resulted in a deduced Gly124-to-Ser (Gly124-Ser) substitution. Second, 4 of the 12 resistant strains (CR4, CR7, CR11, and CR12) carried a G-to-A transition at base 550 that resulted in a deduced Arg184-Gln substitution. The third loci at which lesions were detected occurred in the Thr214 codon, in which two different transitions were observed with two distinct deduced substitutions; the ACA-to-GCA transition resulted in a Thr214-Ala substitution (CR3), whereas the ACA-to-ATA transition resulted in a Thr214-Ile substitution (CR5, CR10). The MICs for GyrB mutants represented by strains CR3, CR4, and CR9 were determined to be 0.2 ug/ml, whereas the MIC for CR5 was 0.3 ug/ml. This suggests that a Thr214-Ile substitution confers a higher level of resistance than Thr214-Ala, Gly124-Ser, or Arg184-Gln, consistent with findings in B. burgdorferi.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [1]

• Molecule Alteration: Missense mutation; p.R184Q
• Resistant Disease: Bartonella bacilliformis infection [ICD-11: 1C11.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Bartonella bacilliformis kC583; 360095
• In Vitro Model: Bartonella bacilliformis strain CR1-CR12; 774
• In Vitro Model: Escherichia coli strain N4177; 562
• In Vitro Model: Escherichia coli strain N99; 562
• In Vitro Model: Escherichia coli strain TOP10F'; 562
• Experiment for Molecule Alteration: DNA hybridizations assay
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: First, in 5 of the 12 coumermycin A1-resistant strains (CR1, CR2, CR6, CR8, and CR9), identical G-to-A transitions at base 370 of the 2,079-bp ORF resulted in a deduced Gly124-to-Ser (Gly124-Ser) substitution. Second, 4 of the 12 resistant strains (CR4, CR7, CR11, and CR12) carried a G-to-A transition at base 550 that resulted in a deduced Arg184-Gln substitution. The third loci at which lesions were detected occurred in the Thr214 codon, in which two different transitions were observed with two distinct deduced substitutions; the ACA-to-GCA transition resulted in a Thr214-Ala substitution (CR3), whereas the ACA-to-ATA transition resulted in a Thr214-Ile substitution (CR5, CR10). The MICs for GyrB mutants represented by strains CR3, CR4, and CR9 were determined to be 0.2 ug/ml, whereas the MIC for CR5 was 0.3 ug/ml. This suggests that a Thr214-Ile substitution confers a higher level of resistance than Thr214-Ala, Gly124-Ser, or Arg184-Gln, consistent with findings in B. burgdorferi.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [1]

• Molecule Alteration: Missense mutation; p.Y214A
• Resistant Disease: Bartonella bacilliformis infection [ICD-11: 1C11.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Bartonella bacilliformis kC583; 360095
• In Vitro Model: Bartonella bacilliformis strain CR1-CR12; 774
• In Vitro Model: Escherichia coli strain N4177; 562
• In Vitro Model: Escherichia coli strain N99; 562
• In Vitro Model: Escherichia coli strain TOP10F'; 562
• Experiment for Molecule Alteration: DNA hybridizations assay
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: First, in 5 of the 12 coumermycin A1-resistant strains (CR1, CR2, CR6, CR8, and CR9), identical G-to-A transitions at base 370 of the 2,079-bp ORF resulted in a deduced Gly124-to-Ser (Gly124-Ser) substitution. Second, 4 of the 12 resistant strains (CR4, CR7, CR11, and CR12) carried a G-to-A transition at base 550 that resulted in a deduced Arg184-Gln substitution. The third loci at which lesions were detected occurred in the Thr214 codon, in which two different transitions were observed with two distinct deduced substitutions; the ACA-to-GCA transition resulted in a Thr214-Ala substitution (CR3), whereas the ACA-to-ATA transition resulted in a Thr214-Ile substitution (CR5, CR10). The MICs for GyrB mutants represented by strains CR3, CR4, and CR9 were determined to be 0.2 ug/ml, whereas the MIC for CR5 was 0.3 ug/ml. This suggests that a Thr214-Ile substitution confers a higher level of resistance than Thr214-Ala, Gly124-Ser, or Arg184-Gln, consistent with findings in B. burgdorferi.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [1]

• Molecule Alteration: Missense mutation; p.Y214I
• Resistant Disease: Bartonella bacilliformis infection [ICD-11: 1C11.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Bartonella bacilliformis kC583; 360095
• In Vitro Model: Bartonella bacilliformis strain CR1-CR12; 774
• In Vitro Model: Escherichia coli strain N4177; 562
• In Vitro Model: Escherichia coli strain N99; 562
• In Vitro Model: Escherichia coli strain TOP10F'; 562
• Experiment for Molecule Alteration: DNA hybridizations assay
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: First, in 5 of the 12 coumermycin A1-resistant strains (CR1, CR2, CR6, CR8, and CR9), identical G-to-A transitions at base 370 of the 2,079-bp ORF resulted in a deduced Gly124-to-Ser (Gly124-Ser) substitution. Second, 4 of the 12 resistant strains (CR4, CR7, CR11, and CR12) carried a G-to-A transition at base 550 that resulted in a deduced Arg184-Gln substitution. The third loci at which lesions were detected occurred in the Thr214 codon, in which two different transitions were observed with two distinct deduced substitutions; the ACA-to-GCA transition resulted in a Thr214-Ala substitution (CR3), whereas the ACA-to-ATA transition resulted in a Thr214-Ile substitution (CR5, CR10). The MICs for GyrB mutants represented by strains CR3, CR4, and CR9 were determined to be 0.2 ug/ml, whereas the MIC for CR5 was 0.3 ug/ml. This suggests that a Thr214-Ile substitution confers a higher level of resistance than Thr214-Ala, Gly124-Ser, or Arg184-Gln, consistent with findings in B. burgdorferi.

References

• Ref 1: Mutations in Bartonella bacilliformis gyrB confer resistance to coumermycin A1. Antimicrob Agents Chemother. 1998 Nov;42(11):2906-13. doi: 10.1128/AAC.42.11.2906.
• Ref 2: gyrB mutations which confer coumarin resistance also affect DNA supercoiling and ATP hydrolysis by Escherichia coli DNA gyrase. Mol Microbiol. 1992 Jun;6(12):1617-24. doi: 10.1111/j.1365-2958.1992.tb00886.x.