Drug Information

Drug (ID: DG00238) and It's Reported Resistant Information

• Name: Novobiocin
• Synonyms: Albamix; Albamycin; Cardelmycin; Cathocin; Cathomycin; Inamycin; NOV; Novobiocina; Novobiocine; Novobiocinum; Robiocina; Sirbiocina; Spheromycin; Stilbiocina; Streptonivicin; Crystallinic acid; Novobiocin sodium salt; PA 93; U 6391; Albamycin (TN); Antibiotic PA-93; Novo-R; Novobiocin [INN:BAN]; Novobiocina [INN-Spanish]; Novobiocine [INN-French]; Novobiocinum [INN-Latin]; Streptonivicin (*Sodium salt*); [(3R,4S,5R,6R)-5-hydroxy-6-[2-hydroxy-3-[[4-hydroxy-3-(3-methylbut-2-enyl)benzoyl]amino]-8-methyl-4-oxochromen-7-yl]oxy-3-methoxy-2,2-dimethyloxan-4-yl] carbamate; N-[7-[[3-O-(Aminocarbonyl)-6-deoxy-5-C-methyl-4-O-methyl-.beta.-L-lyxo-hexopyranosyl]oxy]-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-yl]-4-hydroxy-3-(3-methyl-2-butenyl); (3R,4S,5R,6R)-5-hydroxy-6-{[4-hydroxy-3-({[4-hydroxy-3-(3-methylbut-2-en-1-yl)phenyl]carbonyl}amino)-8-methyl-2-oxo-2H-chromen-7-yl]oxy}-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate; (3r,4s,5r,6r)-5-hydroxy-6-[(2-hydroxy-3-{[4-hydroxy-3-(3-methylbut-2-en-1-yl)benzoyl]amino}-8-methyl-4-oxo-4h-chromen-7-yl)oxy]-3-methoxy-2,2-dimethyltetrahydro-2h-pyran-4-yl carbamate(non-preferred name); 7-(3-(O-Carbamoyl)-4-(O-methyl)-5,5-dimethyl-alpha-L-lyxopyranosyloxy)-4-hydroxy-3-(4-hydroxy-3-(3-methyl-2-butenyl)benzamidol)-8-methylcumarin; 7-(Carbamoyltetrahydro-3-hydroxy-5-methoxy-6,6-dimethylpyran-2-yloxy)-4-hydroxy-3-(4-hydroxy-3-(3-methylbut-2-enyl)benzamide)-8-methyl-2H-chromen-2-one
• 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 (3 diseases)
  Pneumonia [ICD-11: CA40]; [1]
  Salmonellosis [ICD-11: 1A09]; [2]
  Staphylococcus meningitis [ICD-11: 1B54]; [3]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [4]
• Target: DNA topoisomerase II (TOP2); TOP2A_HUMAN TOP2B_HUMAN; [1]
• Formula: C31H36N2O11
• IsoSMILES: CC1=C(C=CC2=C1OC(=O)C(=C2O)NC(=O)C3=CC(=C(C=C3)O)CC=C(C)C)O[C@H]4[C@@H]([C@@H]([C@H](C(O4)(C)C)OC)OC(=O)N)O
• InChI: 1S/C31H36N2O11/c1-14(2)7-8-16-13-17(9-11-19(16)34)27(37)33-21-22(35)18-10-12-20(15(3)24(18)42-28(21)38)41-29-23(36)25(43-30(32)39)26(40-6)31(4,5)44-29/h7,9-13,23,25-26,29,34-36H,8H2,1-6H3,(H2,32,39)(H,33,37)/t23-,25+,26-,29-/m1/s1
• InChIKey: YJQPYGGHQPGBLI-KGSXXDOSSA-N
• PubChem CID: 54675769
• ChEBI ID: CHEBI:28368
• TTD Drug ID: D0Q0PR
• DrugBank ID: DB01051

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  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

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA gyrase subunit B (GYRB) [4]

• 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.

Salmonellosis [ICD-11: 1A09]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein MdtC (MDTC) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enterica serovar Typhimurium ATCC 14028s; 588858
• Experiment for Molecule Alteration: Quantitative real-time PCR
• Experiment for Drug Resistance: L agar plate method assay
• Mechanism Description: Overexpression or overproduction of mdtABC confers drug resistance.

Key Molecule: Multidrug resistance protein MdtB (MDTB) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enterica serovar Typhimurium ATCC 14028s; 588858
• Experiment for Molecule Alteration: Quantitative real-time PCR
• Experiment for Drug Resistance: L agar plate method assay
• Mechanism Description: Overexpression or overproduction of mdtABC confers drug resistance.

Key Molecule: Multidrug resistance protein MdtA (MDTA) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enterica serovar Typhimurium ATCC 14028s; 588858
• Experiment for Molecule Alteration: Quantitative real-time PCR
• Experiment for Drug Resistance: L agar plate method assay
• Mechanism Description: Overexpression or overproduction of mdtABC confers drug resistance.

Key Molecule: Efflux pump membrane transporter (ACRD) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enterica serovar Typhimurium ATCC 14028s; 588858
• Experiment for Molecule Alteration: Quantitative real-time PCR
• Experiment for Drug Resistance: L agar plate method assay
• Mechanism Description: Overexpression or overproduction of acrD confers drug resistance.

Key Molecule: Multidrug export protein EmrA (EMRA) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enterica serovar Typhimurium ATCC 14028s; 588858
• Experiment for Molecule Alteration: Quantitative real-time PCR
• Experiment for Drug Resistance: L agar plate method assay
• Mechanism Description: Overexpression or overproduction of emrAB confers drug resistance.

Key Molecule: Multidrug export protein EmrB (EMRB) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enterica serovar Typhimurium ATCC 14028s; 588858
• Experiment for Molecule Alteration: Quantitative real-time PCR
• Experiment for Drug Resistance: L agar plate method assay
• Mechanism Description: Overexpression or overproduction of emrAB confers drug resistance.

Key Molecule: Efflux pump membrane transporter MdsA (MDSA) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enterica serovar Typhimurium ATCC 14028s; 588858
• Experiment for Molecule Alteration: Quantitative real-time PCR
• Experiment for Drug Resistance: L agar plate method assay
• Mechanism Description: Overexpression or overproduction of MdsABC confers drug resistance.

Key Molecule: Efflux pump membrane transporter MdsB (MDSB) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enterica serovar Typhimurium ATCC 14028s; 588858
• Experiment for Molecule Alteration: Quantitative real-time PCR
• Experiment for Drug Resistance: L agar plate method assay
• Mechanism Description: Overexpression or overproduction of MdsABC confers drug resistance.

Key Molecule: Efflux pump membrane transporter MdsC (MDSC) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Salmonella enterica infection [ICD-11: 1A09.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Salmonella enterica serovar Typhimurium ATCC 14028s; 588858
• Experiment for Molecule Alteration: Quantitative real-time PCR
• Experiment for Drug Resistance: L agar plate method assay
• Mechanism Description: Overexpression or overproduction of MdsABC confers drug resistance.

Staphylococcus meningitis [ICD-11: 1B54]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [3]

• Molecule Alteration: Missense mutation; p.G78S
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: Twofold agar dilution method assay
• Mechanism Description: At first, successive point mutations specifically occurred in gyrB; next, a point mutation occurred in parE; finally, a point mutation occurred in gyrB again. The accumulation of mutations in both the gyrB and the parE genes is associated with high-level resistance to novobiocin.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [3]

• Molecule Alteration: Missense mutation; p.R136G
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: Twofold agar dilution method assay
• Mechanism Description: At first, successive point mutations specifically occurred in gyrB; next, a point mutation occurred in parE; finally, a point mutation occurred in gyrB again. The accumulation of mutations in both the gyrB and the parE genes is associated with high-level resistance to novobiocin.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [3]

• Molecule Alteration: Missense mutation; p.A89G
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: Twofold agar dilution method assay
• Mechanism Description: At first, successive point mutations specifically occurred in gyrB; next, a point mutation occurred in parE; finally, a point mutation occurred in gyrB again. The accumulation of mutations in both the gyrB and the parE genes is associated with high-level resistance to novobiocin.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [3]

• Molecule Alteration: Missense mutation; p.S128L
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• Experiment for Molecule Alteration: PCR amplification and DNA sequence assay
• Experiment for Drug Resistance: Twofold agar dilution method assay
• Mechanism Description: At first, successive point mutations specifically occurred in gyrB; next, a point mutation occurred in parE; finally, a point mutation occurred in gyrB again. The accumulation of mutations in both the gyrB and the parE genes is associated with high-level resistance to novobiocin.

ICD-12: Respiratory system diseases

Pneumonia [ICD-11: CA40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug efflux SMR transporter (ABES) [1]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Acinetobacter baumannii infection [ICD-11: CA40.4]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli kAM32; 562
• Experiment for Molecule Alteration: Fluorometric efflux assay
• Experiment for Drug Resistance: Broth dilution assay
• Mechanism Description: The abeS gene product conferred resistance to various antimicrobial compounds through an efflux mechanism.

References

• Ref 1: Role of AbeS, a novel efflux pump of the SMR family of transporters, in resistance to antimicrobial agents in Acinetobacter baumannii. Antimicrob Agents Chemother. 2009 Dec;53(12):5312-6. doi: 10.1128/AAC.00748-09. Epub 2009 Sep 21.
• Ref 2: Virulence and drug resistance roles of multidrug efflux systems of Salmonella enterica serovar Typhimurium. Mol Microbiol. 2006 Jan;59(1):126-41. doi: 10.1111/j.1365-2958.2005.04940.x.
• Ref 3: Accumulation of mutations in both gyrB and parE genes is associated with high-level resistance to novobiocin in Staphylococcus aureus. Antimicrob Agents Chemother. 2005 Sep;49(9):3810-5. doi: 10.1128/AAC.49.9.3810-3815.2005.
• Ref 4: 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.