Details of the Drug Combination

General Information of Drug Combination (ID: DC068IR)

• Drug Combination Name: Framycetin + Metronidazole
• Indication: Colorectal Neoplasms; Status: Phase 1 [1]
• Component Drugs:
  Framycetin (DMF8DNE): Small molecular drug
  Metronidazole (DMTIVEN): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Framycetin

Disease Entry	ICD 11	Status	REF
Acute liver failure	DB91	Approved	[2]
Alcoholic cirrhosis of liver	DB94	Approved	[2]
Bacterial infection	1A00-1C4Z	Approved	[3]
Blepharoconjunctivitis	N.A.	Approved	[4]
Corneal abrasion	NA06.4	Approved	[4]
Hepatic coma	N.A.	Approved	[4]
Hepatic encephalopathy	DB99.5	Approved	[4]
Keratitis	N.A.	Approved	[5]
Urinary tract infection	GC08	Approved	[6]
Uveitis	9A96.Z	Investigative	[4]

Framycetin Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial 16S ribosomal RNA (Bact 16S rRNA)	TT38DW5	NOUNIPROTAC	Binder	[11]
Staphylococcus 30S ribosomal subunit (Stap-coc pbp2)	TTQ8KVI	F4NA87_STAAU	Binder	[12]

Framycetin Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Aminoglycoside O-phosphotransferase (aphA6)	DEWPAJD	KKA6_ACIBA	Metabolism	[13]
Aminoglycoside N-acetyltransferase (aacC2)	DEJADS9	AAC6_ACIBA	Metabolism	[13]

Framycetin Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
T-lymphocyte activation antigen CD86 (CD86)	OTJCSBPC	CD86_HUMAN	Increases Expression	[14]
N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15)	OT53SIZG	NAA15_HUMAN	Increases ADR	[15]
Glial fibrillary acidic protein (GFAP)	OTQ01ZAS	GFAP_HUMAN	Increases ADR	[15]

Indication(s) of Metronidazole

Disease Entry	ICD 11	Status	REF
Abscess	N.A.	Approved	[7]
Amoebiasis	1A36	Approved	[8]
Anaerobic bacteria infectious disease	N.A.	Approved	[7]
Bacteremia	1A73	Approved	[7]
Bacterial vaginosis	MF3A	Approved	[7]
Bladder squamous cell carcinoma	N.A.	Approved	[7]
Endometritis	N.A.	Approved	[7]
Liver abscess (disease)	N.A.	Approved	[7]
Peritonitis	N.A.	Approved	[7]
Trichomoniasis	N.A.	Approved	[7]
Crohn disease	DD70	Phase 3	[9]
Perianal crohn disease	DD70.4	Phase 3	[10]
Giardiasis	N.A.	Investigative	[7]

Metronidazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Deoxyribonucleic acid (Bact DNA)	TTS1W4A	NOUNIPROTAC	Modulator	[16]

Metronidazole Interacts with 14 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[17]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[18]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[19]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[19]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[19]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[20]
Nitroreductase (NTR)	DE8R7QY	A0A482G3K9_GIAIN	Metabolism	[21]
Nitroreductase (NTR)	DE2VSMT	A2DZ34_TRIVA	Metabolism	[21]
Nitroreductase (NTR)	DEQGIMN	A4K8Z3_ENTHI	Metabolism	[21]
Nitroreductase (NTR)	DEP7ECA	B1R7B9_CLOPF	Metabolism	[22]
Nitroreductase (NTR)	DEAN5EW	NFSB_ENTCL	Metabolism	[23]
Nitroreductase (NTR)	DE3U2Y6	A0A377KR04_ENTCA	Metabolism	[24]
Nitroreductase (NTR)	DEUW4J0	A0A376H6M5_ENTGA	Metabolism	[24]
Nitroreductase (NTR)	DELAPDY	A0A1C0X0J8_BACFG	Metabolism	[25]

Metronidazole Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[26]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1)	OTRGGIFP	DRB1_HUMAN	Affects Expression	[27]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1)	OTVVI3UI	DQB1_HUMAN	Affects Expression	[27]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[26]

References

• [1] ClinicalTrials.gov (NCT03042091) Neomycin and Metronidazole Hydrochloride With or Without Polyethylene Glycol in Reducing Infection in Patients Undergoing Elective Colorectal Surgery
• [2] 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: 709).
• [3] Drug information of Framycetin, 2008. eduDrugs.
• [4] A standard database for drug repositioning. Sci Data. 2017 Mar 14;4:170029.
• [5] Bacterial isolates, antimicrobial susceptibility, and clinical characteristics of bacterial keratitis in dogs presenting to referral practice in Australia. Vet Ophthalmol. 2016 Sep;19(5):418-26.
• [6] Prostatectomy and infection. J Urol. 1971 Dec;106(6):910-2.
• [7] Metronidazole FDA Label
• [8] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 018517.
• [9] ClinicalTrials.gov (NCT00509639) Evaluation of Topical 10% Metronidazole Ointment for the Treatment of Active Perianal Crohn's Disease. U.S. National Institutes of Health.
• [10] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [11] Antistaphylococcal activity of gentamicin. Minerva Med. 1975 Dec 8;66(84):4505-26.
• [12] Characterization of a 30S ribosomal subunit assembly intermediate found in Escherichia coli cells growing with neomycin or paromomycin. Arch Microbiol. 2008 May;189(5):441-9.
• [13] Relationship between antimicrobial resistance and aminoglycoside-modifying enzyme gene expressions in Acinetobacter baumannii. Chin Med J (Engl). 2005 Jan 20;118(2):141-5.
• [14] A plasmacytoid dendritic cell (CD123+/CD11c-) based assay system to predict contact allergenicity of chemicals. Toxicology. 2009 Oct 1;264(1-2):1-9. doi: 10.1016/j.tox.2009.07.021. Epub 2009 Aug 7.
• [15] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [16] DNA breakage due to metronidazole treatment. Mutat Res. 2001 Jul 1;478(1-2):153-8.
• [17] Does metronidazole interact with CYP3A substrates by inhibiting their metabolism through this metabolic pathway? Or should other mechanisms be considered? Ann Pharmacother. 2007 Apr;41(4):653-8.
• [18] Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.
• [19] The role of human cytochrome P450 enzymes in the formation of 2-hydroxymetronidazole: CYP2A6 is the high affinity (low Km) catalyst. Drug Metab Dispos. 2013 Sep;41(9):1686-94.
• [20] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [21] Giardia, Entamoeba, and Trichomonas enzymes activate metronidazole (nitroreductases) and inactivate metronidazole (nitroimidazole reductases). Antimicrob Agents Chemother. 2009 Feb;53(2):458-64.
• [22] Acetamide--a metabolite of metronidazole formed by the intestinal flora. Biochem Pharmacol. 1979 Dec 15;28(24):3611-5.
• [23] Overexpression, isotopic labeling, and spectral characterization of Enterobacter cloacae nitroreductase. Protein Expr Purif. 1998 Jun;13(1):53-60.
• [24] Mechanism of metronidazole-resistance by isolates of nitroreductase-producing Enterococcus gallinarum and Enterococcus casseliflavus from the human intestinal tract. FEMS Microbiol Lett. 2003 Aug 29;225(2):195-200.
• [25] Isolation of metronidazole-resistant Bacteroides fragilis carrying the nimA nitroreductase gene from a patient in Washington State. J Clin Microbiol. 2004 Sep;42(9):4127-9. Case Reports
• [26] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [27] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.