Drug Information

Drug (ID: DG00209) and It's Reported Resistant Information

• Name: Sparfloxacin
• Synonyms: Esparfloxacino; SPFX; Spara; Sparfloxacine; Sparfloxacinum; Zagam; AT 4140; CP 103826; PD 131501; PD131501; AT-4140; CP-103826; DRG-0143; Esparfloxacino [INN-Spanish]; Liposome-encapsulated sparfloxacin; PD 1315-1; PD-131501; RP-64206; Respipac (TN); Sparfloxacin & RU 40555; Sparfloxacine [INN-French]; Sparfloxacinum [INN-Latin]; Zagam (TN); Sparfloxacin, cis-isomer; Sparfloxacin (JAN/USAN/INN); Sparfloxacin [USAN:BAN:INN:JAN]; Cis-5-Amino-1-cyclopropyl-7-(3,5-dimethyl-1-piperazinyl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid; (cis)-5-amino-1-cyclopropyl-7-(3,5-dimethyl-1-piperazinyl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid; 5-Amino-1-cyclohexyl-7-(cis-3,5-dimethylpiperazino)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid; 5-Amino-1-cyclopropyl-7-(cis-3,5-dimethyl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid & RU 40555; 5-Amino-1-cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid; 5-amino-1-cyclopropyl-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 5-amino-1-cyclopropyl-7-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-6,8-difluoro-4-oxoquinoline-3-carboxylic acid
• 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 (4 diseases)
  Mycobacterial diseases [ICD-11: 1B2Z ]; [1]
  Pneumonia [ICD-11: CA40]; [2]
  Prostate cancer [ICD-11: 2C82]; [1]
  Staphylococcus meningitis [ICD-11: 1B54]; [3]
• Target: Bacterial DNA gyrase (Bact gyrase); GYRA_STAAU GYRB_STAAU; [1]
• Target: Staphylococcus Topoisomerase IV (Stap-coc parC); PARC_STAAS; [1]
• Formula: C19H22F2N4O3
• IsoSMILES: C[C@@H]1CN(C[C@@H](N1)C)C2=C(C(=C3C(=C2F)N(C=C(C3=O)C(=O)O)C4CC4)N)F
• InChI: 1S/C19H22F2N4O3/c1-8-5-24(6-9(2)23-8)17-13(20)15(22)12-16(14(17)21)25(10-3-4-10)7-11(18(12)26)19(27)28/h7-10,23H,3-6,22H2,1-2H3,(H,27,28)/t8-,9+
• InChIKey: DZZWHBIBMUVIIW-DTORHVGOSA-N
• PubChem CID: 60464
• ChEBI ID: CHEBI:9212
• TTD Drug ID: D0K6GZ
• VARIDT ID: DR00791
• DrugBank ID: DB01208

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

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Mycobacterial diseases [ICD-11: 1B2Z ]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA topoisomerase (ATP-hydrolyzing) (PARC) [1]

• Molecule Alteration: Missense mutation; p.K134R
• Resistant Disease: Mycoplasma hominis genital infection [ICD-11: 1B2Z.7]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycoplasma hominis ATCC 23114(PG21); 347256
• In Vitro Model: Mycoplasma hominis isolate; 2098
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The single amino acid mutation in ParC of MH may relate to the resistance to OFX and LVX and the high-level resistance to fluoroquinolones for MH is associated with mutations in both DNA gyrase and the ParC subunit of topoisomerase IV.

Key Molecule: DNA topoisomerase (ATP-hydrolyzing) (PARC) [1]

• Molecule Alteration: Missense mutation; p.K134R
• Resistant Disease: Mycoplasma hominis mycoplasma infection [ICD-11: 1B2Z.4]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycoplasma hominis ATCC 23114(PG21); 347256
• In Vitro Model: Mycoplasma hominis isolate; 2098
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The single amino acid mutation in ParC of MH may relate to the resistance to OFX and LVX and the high-level resistance to fluoroquinolones for MH is associated with mutations in both DNA gyrase and the ParC subunit of topoisomerase IV.

Staphylococcus meningitis [ICD-11: 1B54]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Quinolone resistance protein NorB (NORB) [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• Experiment for Molecule Alteration: DNA microarray hybridization assay
• Experiment for Drug Resistance: Serial twofold agar dilutions assay
• Mechanism Description: MgrA was an indirect regulator of norB expression. The mgrA norB double mutant was reproducibly twofold more susceptible to the tested quinolones than the mgrA mutant.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: HTH-type transcriptional regulator MgrA (MGRA) [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Staphylococcus aureus infection [ICD-11: 1B54.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• Experiment for Molecule Alteration: DNA microarray hybridization assay
• Experiment for Drug Resistance: Serial twofold agar dilutions assay
• Mechanism Description: MgrA was an indirect regulator of norB expression. The mgrA norB double mutant was reproducibly twofold more susceptible to the tested quinolones than the mgrA mutant.

ICD-02: Benign/in-situ/malignant neoplasm

Prostate cancer [ICD-11: 2C82]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DNA topoisomerase (ATP-hydrolyzing) (PARC) [1]

• Molecule Alteration: Missense mutation; p.K134R
• Resistant Disease: Mycoplasma hominis prostate cancer [ICD-11: 2C82.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycoplasma hominis ATCC 23114(PG21); 347256
• In Vitro Model: Mycoplasma hominis isolate; 2098
• Experiment for Molecule Alteration: Whole genome sequence assay
• Mechanism Description: The single amino acid mutation in ParC of MH may relate to the resistance to OFX and LVX and the high-level resistance to fluoroquinolones for MH is associated with mutations in both DNA gyrase and the ParC subunit of topoisomerase IV.

ICD-12: Respiratory system diseases

Pneumonia [ICD-11: CA40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [2]

• Molecule Alteration: Missense mutation; p.D84H (GAT-CAT)
• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [2]

• Molecule Alteration: Missense mutation; p.S80Y (TCT-TAT)
• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Key Molecule: DNA topoisomerase 4 subunit A (PARC) [2]

• Molecule Alteration: Missense mutation; p.S80F (TCT-TTT)
• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: Mutations in parC were detected in the two resistant mutants obtained in vivo (BM4203-R andBM4204-R) as well as in two (BM4203-R1 and BM4203-R2) of the six mutants obtained in vitro. These mutations led to Ser-80-Tyr or Phe or to Asp-84-His substitutions(S. aureus coordinates) that are either identical or similar to those found in low-level-resistant parC mutations of S. aureus:Ser-80-Tyr or Phe and Glu-84-Lys or Leu.

Key Molecule: DNA gyrase subunit A (GYRA) [2]

• Molecule Alteration: Missense mutation; p.S843F (TCC-TTC)
• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Streptococcus pneumoniae strain BM4203-BM4203-R; 1313
• In Vitro Model: Streptococcus pneumoniae strain BM4204-BM4204-R; 1313
• Experiment for Molecule Alteration: Sequence analysis
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: An additional mutant obtained in vitro, BM4205-R3, displayed a higher level of fluoroquinolone resistance and had a mutation in gyrA leading to a Ser-84-Phe change.

References

• Ref 1: Molecular mechanism of fluoroquinolones resistance in Mycoplasma hominis clinical isolates. Braz J Microbiol. 2014 May 19;45(1):239-42. doi: 10.1590/s1517-83822014000100034. eCollection 2014.
• Ref 2: Contribution of mutations in gyrA and parC genes to fluoroquinolone resistance of mutants of Streptococcus pneumoniae obtained in vivo and in vitro. Antimicrob Agents Chemother. 1996 Nov;40(11):2505-10. doi: 10.1128/AAC.40.11.2505.
• Ref 3: MgrA is a multiple regulator of two new efflux pumps in Staphylococcus aureus. J Bacteriol. 2005 Apr;187(7):2395-405. doi: 10.1128/JB.187.7.2395-2405.2005.