Details of the Drug Combination

General Information of Drug Combination (ID: DC69VWO)

• Drug Combination Name: Vancomycin + Metronidazole
• Indication: Clostridium Difficile; Status: Phase 2 [1]
• Component Drugs:
  Vancomycin (DM3JFIH): N.A.
  Metronidazole (DMTIVEN): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Vancomycin

Disease Entry	ICD 11	Status	REF
Bacteremia	1A73	Approved	[2]
Bacterial endocarditis	N.A.	Approved	[2]
Clostridioides difficile infection	1A04	Approved	[2]
Methicillin-resistant staphylococci infection	1A00-1A09	Approved	[3]
Neonatal sepsis	N.A.	Approved	[2]
Staphylococcal pneumonia	N.A.	Approved	[2]
Staphylococcus aureus infection	N.A.	Approved	[2]
MRSA infection	1D01.0Y	Investigative	[4]
Skin infection	1F28-1G0Z	Investigative	[2]

Vancomycin Interacts with 14 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
VanA ligase (vanA)	DEOFMQ7	Q0WYK7_ENTFL	Metabolism	[9]
VanA ligase (vanA)	DEO97D6	VANA_ENTFC	Metabolism	[9]
VanB ligase (vanB)	DE27YVU	Q58F99_ENTFC	Metabolism	[9]
VanC2 ligase (vanC)	DEIF4P9	VANC_ENTGA	Metabolism	[10]
VanG ligase (vanG)	DEPH3S7	A0A076ZC24_STRAP	Metabolism	[11]
VanA ligase (vanA)	DEO8E75	A0A437UFE2_ENTAV	Metabolism	[9]
VanB ligase (vanB)	DER7KFQ	VANB_ENTFA	Metabolism	[9]
VanC2 ligase (vanC)	DEH73ZC	Q47720_ENTCA	Metabolism	[12]
D-alanylalanine synthetase (ddl)	DE035GU	A0A1Q6S944_9FIRM	Metabolism	[11]
VanG ligase (vanG)	DEPN8F9	A0A076YRI6_STRAG	Metabolism	[11]
VanB ligase (vanB)	DEMDEJ8	Q58F99_ENTFC	Metabolism	[13]
VanB ligase (vanB)	DE2GMEK	Q58F99_ENTFC	Metabolism	[13]
VanA ligase (vanA)	DEN6VO0	A0A376GZ73_ENTGA	Metabolism	[14]
VanA ligase (vanA)	DESOXHP	A0A4U9YK96_ENTCA	Metabolism	[15], [14]

Vancomycin Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
HLA class I histocompatibility antigen, B alpha chain (HLA-B)	OTNXFWY2	HLAB_HUMAN	Affects Expression	[16]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[17]
HLA class II histocompatibility antigen, DM beta chain (HLA-DMB)	OT17HGXJ	DMB_HUMAN	Affects Expression	[16]
Major histocompatibility complex class I-related gene protein (MR1)	OTZU3XX7	HMR1_HUMAN	Affects Expression	[16]

Indication(s) of Metronidazole

Disease Entry	ICD 11	Status	REF
Abscess	N.A.	Approved	[5]
Amoebiasis	1A36	Approved	[6]
Anaerobic bacteria infectious disease	N.A.	Approved	[5]
Bacteremia	1A73	Approved	[5]
Bacterial vaginosis	MF3A	Approved	[5]
Bladder squamous cell carcinoma	N.A.	Approved	[5]
Endometritis	N.A.	Approved	[5]
Liver abscess (disease)	N.A.	Approved	[5]
Peritonitis	N.A.	Approved	[5]
Trichomoniasis	N.A.	Approved	[5]
Crohn disease	DD70	Phase 3	[7]
Perianal crohn disease	DD70.4	Phase 3	[8]
Giardiasis	N.A.	Investigative	[5]

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	[18]

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	[19]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[20]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[21]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[21]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[21]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[22]
Nitroreductase (NTR)	DE8R7QY	A0A482G3K9_GIAIN	Metabolism	[23]
Nitroreductase (NTR)	DE2VSMT	A2DZ34_TRIVA	Metabolism	[23]
Nitroreductase (NTR)	DEQGIMN	A4K8Z3_ENTHI	Metabolism	[23]
Nitroreductase (NTR)	DEP7ECA	B1R7B9_CLOPF	Metabolism	[24]
Nitroreductase (NTR)	DEAN5EW	NFSB_ENTCL	Metabolism	[25]
Nitroreductase (NTR)	DE3U2Y6	A0A377KR04_ENTCA	Metabolism	[26]
Nitroreductase (NTR)	DEUW4J0	A0A376H6M5_ENTGA	Metabolism	[26]
Nitroreductase (NTR)	DELAPDY	A0A1C0X0J8_BACFG	Metabolism	[27]

Metronidazole Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[28]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1)	OTRGGIFP	DRB1_HUMAN	Affects Expression	[16]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1)	OTVVI3UI	DQB1_HUMAN	Affects Expression	[16]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[28]

References

• [1] ClinicalTrials.gov (NCT02466698) Intestinal Lavage for the Treatment of Severe C. Difficile Infections
• [2] Vancomycin FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [5] Metronidazole FDA Label
• [6] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 018517.
• [7] ClinicalTrials.gov (NCT00509639) Evaluation of Topical 10% Metronidazole Ointment for the Treatment of Active Perianal Crohn's Disease. U.S. National Institutes of Health.
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] Genetics and mechanisms of glycopeptide resistance in enterococci. Antimicrob Agents Chemother. 1993 Aug;37(8):1563-71.
• [10] Sequence of the vanC gene of Enterococcus gallinarum BM4174 encoding a D-alanine:D-alanine ligase-related protein necessary for vancomycin resistance. Gene. 1992 Mar 1;112(1):53-8.
• [11] vanG element insertions within a conserved chromosomal site conferring vancomycin resistance to Streptococcus agalactiae and Streptococcus anginosus. mBio. 2014 Jul 22;5(4):e01386-14.
• [12] Bacterial resistance to vancomycin: overproduction, purification, and characterization of VanC2 from Enterococcus casseliflavus as a D-Ala-D-Ser ligase. Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10040-4.
• [13] vanI: a novel D-Ala-D-Lac vancomycin resistance gene cluster found in Desulfitobacterium hafniense. Microb Biotechnol. 2014 Sep;7(5):456-66.
• [14] Emergence of high-level resistance to glycopeptides in Enterococcus gallinarum and Enterococcus casseliflavus. Antimicrob Agents Chemother. 1994 Jul;38(7):1675-7.
• [15] vanA in Enterococcus faecium, Enterococcus faecalis, and Enterococcus casseliflavus detected in French cattle. Foodborne Pathog Dis. 2009 Nov;6(9):1107-11.
• [16] 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.
• [17] [Successful treatment of MRSA-associated glomerulonephritis with antibiotic therapy]. Nihon Jinzo Gakkai Shi. 2003;45(1):37-41.
• [18] DNA breakage due to metronidazole treatment. Mutat Res. 2001 Jul 1;478(1-2):153-8.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [23] Giardia, Entamoeba, and Trichomonas enzymes activate metronidazole (nitroreductases) and inactivate metronidazole (nitroimidazole reductases). Antimicrob Agents Chemother. 2009 Feb;53(2):458-64.
• [24] Acetamide--a metabolite of metronidazole formed by the intestinal flora. Biochem Pharmacol. 1979 Dec 15;28(24):3611-5.
• [25] Overexpression, isotopic labeling, and spectral characterization of Enterobacter cloacae nitroreductase. Protein Expr Purif. 1998 Jun;13(1):53-60.
• [26] 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.
• [27] 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
• [28] 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.