Details of the Drug Combination

General Information of Drug Combination (ID: DCQR6Q4)

• Drug Combination Name: Bedaquiline + Pyrazinamide
• Indication: Pulmonary Tuberculosis; Status: Phase 2 [1]
• Component Drugs:
  Bedaquiline (DM3906J): Small molecular drug
  Pyrazinamide (DM4IF32): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Bedaquiline

Disease Entry	ICD 11	Status	REF
Drug-resistant tuberculosis	N.A.	Approved	[2]
Multi-drug resistant tuberculosis	MG52.00	Approved	[3]
Pulmonary tuberculosis	1B10.Z	Approved	[2]

Bedaquiline Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Mycobacterium Proton pump (MycB Prop)	TT19K0L	A0A1Q4HQH4_9MYCO	Modulator	[6]

Bedaquiline Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]

Indication(s) of Pyrazinamide

Disease Entry	ICD 11	Status	REF
Meningeal tuberculosis	N.A.	Approved	[4]
Mycobacterium infection	1B10-1B21	Approved	[5]
Pulmonary tuberculosis	1B10.Z	Approved	[4]

Pyrazinamide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Fatty acid synthetase I (Bact inhA)	TTVTX4N	INHA_MYCTU	Inhibitor	[9]

Pyrazinamide Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[10]
Nicotinamidase (pncA)	DERQS6E	B0VA03_ACIBY	Metabolism	[11]

Pyrazinamide Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase/endoribonuclease IRE1 (ERN1)	OTY9R6FZ	ERN1_HUMAN	Increases Expression	[8]
Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)	OTM0GDTP	IF2A_HUMAN	Increases Phosphorylation	[8]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[8]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[8]
Cyclic AMP-dependent transcription factor ATF-6 alpha (ATF6)	OTAFHAVI	ATF6A_HUMAN	Increases Expression	[8]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[8]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[8]
Solute carrier family 22 member 12 (SLC22A12)	OT72ZAWS	S22AC_HUMAN	Affects Activity	[12]
Eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3)	OT0DZGY4	E2AK3_HUMAN	Increases Phosphorylation	[8]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Tuberculosis, Pulmonary	DC04ZDQ	N. A.	Phase 2	[13]
Pulmonary Tuberculosis	DCDLBJZ	N. A.	Phase 2	[1]
Tuberculosis, Pulmonary	DCFX2VP	N. A.	Phase 2	[14]
Tuberculosis, Pulmonary	DCLYUYV	N. A.	Phase 2	[15]
Tuberculosis	DCV7C4N	N. A.	Phase 2	[16]
Pulmonary Tuberculosis	DCCKTXG	N. A.	Phase 2	[1]
Tuberculosis	DCDBKWI	N. A.	Phase 2	[16]
Pulmonary Tuberculosis	DCZDPWB	N. A.	Phase 1	[17]

References

• [1] ClinicalTrials.gov (NCT01691534) Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis With Clofazimine (C)-TMC207 (J)-PA-824 (Pa)-Pyrazinamide (Z). U.S. National Institutes of Health.
• [2] Bedaquiline FDA Label
• [3] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [4] Pyrazinamide FDA Label
• [5] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7287).
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [7] Bedaquiline metabolism: enzymes and novel metabolites. Drug Metab Dispos. 2014 May;42(5):863-6.
• [8] Pyrazinamide-induced hepatotoxicity is alleviated by 4-PBA via inhibition of the PERK-eIF2-ATF4-CHOP pathway. Toxicology. 2017 Mar 1;378:65-75. doi: 10.1016/j.tox.2017.01.002. Epub 2017 Jan 4.
• [9] Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis. Nat Med. 2000 Sep;6(9):1043-7.
• [10] The metabolism of pyrazoloacridine (NSC 366140) by cytochromes p450 and flavin monooxygenase in human liver microsomes. Clin Cancer Res. 2004 Feb 15;10(4):1471-80.
• [11] Specificity and mechanism of Acinetobacter baumanii nicotinamidase: implications for activation of the front-line tuberculosis drug pyrazinamide. Angew Chem Int Ed Engl. 2009;48(48):9176-9.
• [12] Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol. 2004 Jan;15(1):164-73. doi: 10.1097/01.asn.0000105320.04395.d0.
• [13] ClinicalTrials.gov (NCT05556746) Ultra-Short Course Bedaquiline, Clofazimine, Pyrazinamide and Delamanid Versus Standard Therapy for Drug-Susceptible TB
• [14] ClinicalTrials.gov (NCT03338621) Trial to Evaluate the Efficacy, Safety and Tolerability of BPaMZ in Drug-Sensitive (DS-TB) Adult Patients and Drug-Resistant (DR-TB) Adult Patients
• [15] ClinicalTrials.gov (NCT05766267) Short-course Regimens for the Treatment of Pulmonary Tuberculosis
• [16] ClinicalTrials.gov (NCT02193776) A Phase 2 to Evaluate the Efficacy, Safety and Tolerability of Combinations of Bedaquiline, Moxifloxacin, PA-824 and Pyrazinamide in Adult Subjects With Drug-Sensitive or Multi Drug-Resistant Pulmonary Tuberculosis.
• [17] ClinicalTrials.gov (NCT01215851) Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis With(J-M-Pa-Z) (NC-001)