Drug Information

Drug (ID: DG00318) and It's Reported Resistant Information

• Name: Moxifloxacin
• Synonyms: Avelox; MFX; MXF; MXFX; Vigamox; Avalox (TN); Avelon (TN); Avelox (TN); Moxifloxacin [INN:BAN]; Vigamox (TN); Avelox I.V.; Actira (*Hydrochloride*); Avelox (*Hydrochloride*); (1'S,6'S)-1-Cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-((4aS,7aS)-octahydro-6H-pyrrolo(3,4-b)pyridin-6-yl)-4-oxo-3-quinolinecarboxylic acid; 7-[(4aS,7aS)-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridin-6-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid
• Indication:
  In total 1 Indication(s)
  Bacterial infection [ICD-11: 1A00-1C4Z]; Approved; [1], [2]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (6 diseases)
  Bacterial infection [ICD-11: 1A00-1C4Z]; [3]
  HIV associated with tuberculosis [ICD-11: 1C60]; [1], [2]
  Intra-abdominal infection [ICD-11: DC51]; [4]
  Leprosy [ICD-11: 1B20]; [5]
  Sclerosing cholangitis [ICD-11: DB96]; [6]
  Staphylococcus meningitis [ICD-11: 1B54]; [7]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Anthrax [ICD-11: 1B97]; [8]
• Target: Bacterial DNA gyrase (Bact gyrase); GYRA_STAAU GYRB_STAAU; [1]
• Target: Staphylococcus Topoisomerase IV (Stap-coc parC); PARC_STAAS; [1]
• Formula: C21H24FN3O4
• IsoSMILES: COC1=C2C(=CC(=C1N3C[C@@H]4CCCN[C@@H]4C3)F)C(=O)C(=CN2C5CC5)C(=O)O
• InChI: 1S/C21H24FN3O4/c1-29-20-17-13(19(26)14(21(27)28)9-25(17)12-4-5-12)7-15(22)18(20)24-8-11-3-2-6-23-16(11)10-24/h7,9,11-12,16,23H,2-6,8,10H2,1H3,(H,27,28)/t11-,16+/m0/s1
• InChIKey: FABPRXSRWADJSP-MEDUHNTESA-N
• PubChem CID: 152946
• ChEBI ID: CHEBI:63611
• TTD Drug ID: D0ZV0Z
• VARIDT ID: DR00800
• DrugBank ID: DB00218

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  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

Bacterial infection [ICD-11: 1A00-1C4Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Quinolone efflux pump (QEPA2) [3]

• Molecule Alteration: Missense mutation; p.A99G+p.V134I
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli TOP10; 83333
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: QepA confers decreased susceptibility to hydrophilic fluoroquinolones (e.g., norfloxacin, ciprofloxacin, and enrofloxacin) with a 32- to 64-fold increase of MICs.

Leprosy [ICD-11: 1B20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [5]

• Molecule Alteration: Missense mutation; p.D464N
• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [5]

• Molecule Alteration: Missense mutation; p.N502D
• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [5]

• Molecule Alteration: Missense mutation; p.E504V
• Resistant Disease: Leprosy [ICD-11: 1B20.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli BL21 (DE3); 469008
• In Vitro Model: Escherichia coli Rosetta-gami 2; 562
• In Vitro Model: Escherichia coli TOP-10; 83333
• In Vitro Model: Mycobacterium leprae Thai-53; 1769
• Experiment for Molecule Alteration: Whole genome sequence assay; Allelic frequency measurement assay
• Experiment for Drug Resistance: DNA supercoiling assay; DNA cleavage assay
• Mechanism Description: FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme.The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502.

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) [7]

• 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) [7]

• 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.

Anthrax [ICD-11: 1B97]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA gyrase subunit A (GYRA) [8]

• Molecule Alteration: Mutation; p.S85+p.S85F+p.E89K+p.E89A
• Resistant Disease: Anthrax [ICD-11: 1B97.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli strain; 562
• In Vitro Model: Bacillus anthracis strain; 1392
• Experiment for Molecule Alteration: DNA cleavage assay
• Mechanism Description: The most common gyrase mutations in quinolone-resistant strains of B. anthracis are found at the conserved serine and glutamic acid residues (GyrAS85 and GyrAE89). In laboratory strains selected for resistance against ciprofloxacin and/or moxifloxacin (two widely prescribed quinolone antibacterials), approximately 80% of the isolates carried a GyrAS85L mutation (either alone or in combination with other gyrase/topoisomerase IV amino acid changes). The only other mutation reported to cause resistance without any other gyrase/topoisomerase IV changes was a GyrAE89K substitution.

HIV associated with tuberculosis [ICD-11: 1C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [1], [2]

• Molecule Alteration: Missense mutation; p.N538D
• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Mycobacterium smegmatis LR222; 1772
• In Vitro Model: Mycobacterium tuberculosis MLB 262; 1773
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• In Vitro Model: Mycobacterium tuberculosis liquid; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; disk diffusion test assay
• Mechanism Description: DNA gyrase consists of two GyrA and two GyrB subunits encoded by gyrA and gyrB, respectively.Fluoroquinolone belong to the quinolone class of antibiotics which inhibit bacterial DNA gyrase and topoisomerase IV.Certain gyrA and gyrB mutations reported to confer cross-resistance to different FQ antibiotics based on clinical data have not yet been characterized in well-studied M. tuberculosis backgrounds.

Key Molecule: DNA topoisomerase 4 subunit B (PARE) [1], [2]

• Molecule Alteration: Missense mutation; p.E540D
• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli HB101; 634468
• In Vitro Model: Mycobacterium smegmatis LR222; 1772
• In Vitro Model: Mycobacterium tuberculosis MLB 262; 1773
• In Vitro Model: Mycobacterium tuberculosis isolates; 1773
• In Vitro Model: Mycobacterium tuberculosis liquid; 1773
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay; disk diffusion test assay
• Mechanism Description: DNA gyrase consists of two GyrA and two GyrB subunits encoded by gyrA and gyrB, respectively.Fluoroquinolone belong to the quinolone class of antibiotics which inhibit bacterial DNA gyrase and topoisomerase IV.Certain gyrA and gyrB mutations reported to confer cross-resistance to different FQ antibiotics based on clinical data have not yet been characterized in well-studied M. tuberculosis backgrounds.

References

• Ref 1: Novel gyrase mutations in quinolone-resistant and -hypersusceptible clinical isolates of Mycobacterium tuberculosis: functional analysis of mutant enzymes. Antimicrob Agents Chemother. 2006 Jan;50(1):104-12. doi: 10.1128/AAC.50.1.104-112.2006.
• Ref 2: New insights into fluoroquinolone resistance in Mycobacterium tuberculosis: functional genetic analysis of gyrA and gyrB mutations. PLoS One. 2012;7(6):e39754. doi: 10.1371/journal.pone.0039754. Epub 2012 Jun 28.
• Ref 3: Plasmid-mediated quinolone resistance pump QepA2 in an Escherichia coli isolate from France. Antimicrob Agents Chemother. 2008 Oct;52(10):3801-4. doi: 10.1128/AAC.00638-08. Epub 2008 Jul 21.
• Ref 4: [Progress in the treatment of intra-abdominal anaerobic infection]Zhonghua Wei Chang Wai Ke Za Zhi. 2020 Nov 25;23(11):1028-1031. doi: 10.3760/cma.j.cn.441530-20200812-00478.
• Ref 5: Impact of amino acid substitutions in B subunit of DNA gyrase in Mycobacterium leprae on fluoroquinolone resistance. PLoS Negl Trop Dis. 2012;6(10):e1838. doi: 10.1371/journal.pntd.0001838. Epub 2012 Oct 11.
• Ref 6: Treatment options for other hepatic malignancies .Liver Transpl. 2000 Nov;6(6 Suppl 2):S23-9. doi: 10.1053/jlts.2000.18687. 10.1053/jlts.2000.18687
• Ref 7: 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.
• Ref 8: Interactions between Quinolones and Bacillus anthracis Gyrase and the Basis of Drug Resistance .Biochemistry. 2017 Aug 15;56(32):4191-4200. doi: 10.1021/acs.biochem.7b00203. Epub 2017 Aug 1. 10.1021/acs.biochem.7b00203