Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTIXTO3)

• DTT Name: Staphylococcus Topoisomerase IV (Stap-coc parC)
• Synonyms: Topoisomerase IV subunit A; DNA topoisomerase 4 subunit A
• Gene Name: Stap-coc parC
• DTT Type: Successful target; [1]
• BioChemical Class: Topoisomerase GyrA ParC
• UniProt ID: PARC_STAAS
• TTD ID: T40696
• EC Number: EC 5.6.2.3
• Sequence:
  MSEIIQDLSLEDVLGDRFGRYSKYIIQERALPDVRDGLKPVQRRILYAMYSSGNTHDKNF
  RKSAKTVGDVIGQYHPHGDSSVYEAMVRLSQDWKLRHVLIEMHGNNGSIDNDPPAAMRYT
  EAKLSLLAEELLRDINKETVSFIPNYDDTTLEPMVLPSRFPNLLVNGSTGISAGYATDIP
  PHNLAEVIQATLKYIDNPDITVNQLMKYIKGPDFPTGGIIQGIDGIKKAYESGKGRIIVR
  SKVEEETLRNGRKQLIITEIPYEVNKSSLVKRIDELRADKKVDGIVEVRDETDRTGLRIA
  IELKKDVNSESIKNYLYKNSDLQISYNFNMVAISDGRPKLMGIRQIIDSYLNHQIEVVAN
  RTKFELDNAEKRMHIVEGLIKALSILDKVIELIRSSKNKRDAKENLIEVYEFTEEQAEAI
  VMLQLYRLTNTDIVALEGEHKELEALIKQLRHILDNHDALLNVIKEELNEIKKKFKSERL
  SLIEAEIEEIKIDKEVMVPSEEVILSMTRHGYIKRTSIRSFNASGVEDIGLKDGDSLLKH
  QEVNTQDTVLVFTNKGRYLFIPVHKLADIRWKELGQHVSQIVPIEEDEVVINVFNEKDFN
  TDAFYVFATQNGMIKKSTVPLFKTTRFNKPLIATKVKENDDLISVMRFEKDQLITVITNK
  GMSLTYNTSELSDTGLRAAGVKSINLKAEDFVVVTEGVSENDTILMATQRGSLKRISFKI
  LQVAKRAQRGITLLKELKKNPHRIVAAHVVTGEHSQYTLYSKSNEEHGLINDIHKSEQYT
  NGSFIVDTDDFGEVIDMYIS
• Function: Topoisomerase IV is essential for chromosome segregation. It relaxes supercoiled DNA. Performs the decatenation events required during the replication of a circular DNA molecule.

Molecular Interaction Atlas (MIA) of This DTT

10 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Besifloxacin	DMPHXMI	Ocular inflammation	9C61.24	Approved	[1]
Ciprofloxacin XR	DM2NLS9	Acute gonococcal cervicitis		Approved	[2]
Delafloxacin Meglumine	DMVTU5Q	Acute bacterial skin infection	1C41	Approved	[3]
Finafloxacin	DMZEONG	Urinary tract infection	GC08	Approved	[4]
Gatifloxacin	DMSL679	Acute gonococcal cervicitis		Approved	[2]
Gemifloxacin	DMHT34O	Bacterial infection	1A00-1C4Z	Approved	[2]
Levofloxacin	DMS60RB	Acute maxillary sinusitis		Approved	[2]
Moxifloxacin	DMU8V4S	Bacterial infection	1A00-1C4Z	Approved	[2]
Ozenoxacin	DM6KZMG	Impetigo	1B72	Approved	[5]
Sparfloxacin	DMB4HCT	Bacterial infection	1A00-1C4Z	Approved	[2]

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABT-492	DMJFD2I	Bacterial infection	1A00-1C4Z	Phase 3	[6]
Nemonaxacin	DMIPNBG	Methicillin-resistant staphylococci infection	1A00-1A09	Phase 3	[7]
Zabofloxacin	DMEY1F3	Pneumonia	CA40	Phase 3	[8]
WCK-2349	DMH6XJG	MRSA infection	1D01.0Y	Phase 2	[9]
WCK-771	DMVQARP	Bacterial infection	1A00-1C4Z	Phase 2	[10]
WCK-1152	DMJQHTN	Respiratory tract inflammation	CA07	Phase 1	[11]

4 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Avarofloxacin	DMWA957	Bacterial pneumonia	CA40.0	Discontinued in Phase 2	[12]
DX-619	DMSTA5L	Bacterial infection	1A00-1C4Z	Discontinued in Phase 2	[13]
DK-507k	DME5PXL	Bacterial infection	1A00-1C4Z	Discontinued in Phase 1	[14]
CBR-2092	DMJAGKY	Bacterial infection	1A00-1C4Z	Terminated	[15]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
NSFQ-105	DMSLA8X	Discovery agent	N.A.	Investigative	[16]
Premafloxacin	DMC4W03	Discovery agent	N.A.	Investigative	[17]

References

• [1] Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [3] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [4] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [5] In vitro and in vivo antibacterial activity of T-3912, a novel non-fluorinated topical quinolone. J Antimicrob Chemother. 2002 Mar;49(3):455-65.
• [6] Contrasting Effects of Acidic pH on the Extracellular and Intracellular Activities of the Anti-Gram-Positive Fluoroquinolones Moxifloxacin and Delafloxacin against Staphylococcus aureus
• [7] In vitro activity of nemonoxacin (TG-873870), a novel non-fluorinated quinolone, against clinical isolates of Staphylococcus aureus, enterococci and Streptococcus pneumoniae with various resistance phenotypes in Taiwan.J Antimicrob Chemother.2009 Dec;64(6):1226-9.
• [8] DNA gyrase and topoisomerase IV are dual targets of zabofloxacin in Streptococcus pneumoniae.Int J Antimicrob Agents.2010 Jul;36(1):97-8.
• [9] DOI: 10.1038/ja.2013.86
• [10] Antistaphylococcal Activity of WCK 771, a Tricyclic Fluoroquinolone, in Animal Infection Models
• [11] DOI: 10.1093/jac/dki361
• [12] Antistaphylococcal activities of the new fluoroquinolone JNJ-Q2. Antimicrob Agents Chemother. 2011 Dec;55(12):5512-21.
• [13] DX-619, a novel des-fluoro(6) quinolone manifesting low frequency of selection of resistant Staphylococcus aureus mutants: quinolone resistance beyond modification of type II topoisomerases. Antimicrob Agents Chemother. 2005 Dec;49(12):5051-7.
• [14] In Vitro and In Vivo Antibacterial Activities of DK-507k, a Novel Fluoroquinolone
• [15] In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: studies of the mode of action in Staphylococcus aureus.Antimicrob Agents Chemother.2008 Jul;52(7):2313-23.
• [16] Engineering the specificity of antibacterial fluoroquinolones: benzenesulfonamide modifications at C-7 of ciprofloxacin change its primary target i... Antimicrob Agents Chemother. 2000 Feb;44(2):320-5.
• [17] Alteration of Escherichia coli topoisomerase IV to novobiocin resistance. Antimicrob Agents Chemother. 2003 Mar;47(3):941-7.