Details of the Drug Combination

General Information of Drug Combination (ID: DCOTKBU)

• Drug Combination Name: Ampicillin + Azithromycin
• Indication: Preterm Pre-labor Rupture of Membranes; Status: Phase 1 [1]
• Component Drugs:
  Ampicillin (DMHWE7P): Small molecular drug
  Azithromycin (DMS6UOE): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ampicillin

Disease Entry	ICD 11	Status	REF
Acute epiglottitis	N.A.	Approved	[2]
Acute gonococcal cervicitis	N.A.	Approved	[2]
Acute otitis media	AB00	Approved	[2]
Bacillary dysentery	1A02	Approved	[2]
Bacteremia	1A73	Approved	[2]
Bacterial endocarditis	N.A.	Approved	[2]
Bacterial infection	1A00-1C4Z	Approved	[3]
Cholangitis	N.A.	Approved	[2]
Chorioamnionitis	N.A.	Approved	[2]
Dysentery	N.A.	Approved	[2]
Escherichia coli meningitis	N.A.	Approved	[2]
Meningococcal meningitis	N.A.	Approved	[2]
Peritonitis	N.A.	Approved	[2]
Pneumococcal meningitis	N.A.	Approved	[2]
Staphylococcal pneumonia	N.A.	Approved	[2]
Staphylococcus aureus infection	N.A.	Approved	[2]
Streptococcal pneumonia	N.A.	Approved	[2]
Urinary tract infection	GC08	Approved	[2]
Paratyphoid fever	N.A.	Investigative	[2]
Pelvic inflammatory disease	GA05	Investigative	[2]
Sinusitis	CA0A.Z	Investigative	[2]

Ampicillin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Penicillin binding protein (Bact PBP)	TTJP4SM	NOUNIPROTAC	Binder	[8]

Ampicillin Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[9]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[10]
Peptide transporter 2 (SLC15A2)	DT8QKNP	S15A2_HUMAN	Substrate	[11]

Ampicillin Interacts with 13 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
N-acylhomoserine lactone acylase (lacA)	DEIU0XN	A0A0A1VBK6_9BURK	Metabolism	[12]
Beta-lactamase (blaB)	DET9I1W	BLAC_BACUN	Metabolism	[13]
AmpC beta-lactamase (ampC)	DERI7LO	A0A0H3KQ39_BURM1	Metabolism	[14]
Beta-lactamase (blaB)	DE3FVRW	BLA2_BAC17	Metabolism	[15]
Beta-lactamase (blaB)	DETDS7E	A0A2S0LB67_9FLAO	Metabolism	[15]
Beta-lactamase (blaB)	DEQX0DG	Q8RIK5_FUSNN	Metabolism	[15]
Beta-lactamase (blaB)	DEC7JEF	A0A1S1G219_9NEIS	Metabolism	[15]
Beta-lactamase (blaB)	DEXB2A9	A0A379CPC3_PLESH	Metabolism	[16]
Beta-lactamase (blaB)	DEBKS91	A0A1B1FBM9_ACIBA	Metabolism	[17]
Beta-lactamase (blaB)	DEWMGC3	A0A2U9SV73_9BURK	Metabolism	[15]
Beta-lactamase (blaB)	DEWYT5M	D4HFC4_CUTAS	Metabolism	[15]
Beta-lactamase (blaB)	DE52KD0	Q6EZ46_RALPI	Metabolism	[15]
Beta-lactamase (blaB)	DEG5Y4W	A0A344X3A2_STASP	Metabolism	[15]

Ampicillin Interacts with 77 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Serum paraoxonase/arylesterase 1 (PON1)	OTD0Z2XO	PON1_HUMAN	Decreases Activity	[18]
Phospholemman (FXYD1)	OTNKT6GP	PLM_HUMAN	Increases Expression	[7]
Interferon-related developmental regulator 1 (IFRD1)	OT4SQMLQ	IFRD1_HUMAN	Decreases Expression	[7]
CCN family member 1 (CCN1)	OTKJBEMD	CCN1_HUMAN	Increases Expression	[7]
Calmegin (CLGN)	OTEWVFQV	CLGN_HUMAN	Decreases Expression	[7]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Decreases Expression	[7]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Decreases Expression	[7]
Dickkopf-related protein 1 (DKK1)	OTRDLUSP	DKK1_HUMAN	Increases Expression	[7]
Chloride intracellular channel protein 3 (CLIC3)	OT5KUZ3A	CLIC3_HUMAN	Increases Expression	[7]
Ceruloplasmin (CP)	OTM8JE4Y	CERU_HUMAN	Increases Expression	[7]
Metalloproteinase inhibitor 1 (TIMP1)	OTOXC51H	TIMP1_HUMAN	Decreases Expression	[7]
Cystatin-A (CSTA)	OT1K68KE	CYTA_HUMAN	Decreases Expression	[7]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Expression	[7]
Arginase-1 (ARG1)	OTHZITAM	ARGI1_HUMAN	Increases Expression	[7]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Increases Expression	[7]
Asparagine synthetase (ASNS)	OT8R922G	ASNS_HUMAN	Decreases Expression	[7]
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Increases Expression	[7]
Creatine kinase B-type (CKB)	OTUCKOTT	KCRB_HUMAN	Increases Expression	[7]
Pyruvate kinase PKM (PKM)	OTLHHMC2	KPYM_HUMAN	Increases Expression	[7]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Increases Expression	[7]
Insulin-like growth factor-binding protein 3 (IGFBP3)	OTIX63TX	IBP3_HUMAN	Increases Expression	[7]
Gastricsin (PGC)	OTQRITKI	PEPC_HUMAN	Increases Expression	[7]
Parathymosin (PTMS)	OT9PS4Q0	PTMS_HUMAN	Increases Expression	[7]
Calreticulin (CALR)	OTYD2TR1	CALR_HUMAN	Increases Expression	[7]
Protein-lysine 6-oxidase (LOX)	OT1C2HIU	LYOX_HUMAN	Increases Expression	[7]
Dual specificity protein phosphatase 1 (DUSP1)	OTN6BR75	DUS1_HUMAN	Increases Expression	[7]
Sodium- and chloride-dependent creatine transporter 1 (SLC6A8)	OT88C8JA	SC6A8_HUMAN	Increases Expression	[7]
Glutamate--cysteine ligase catalytic subunit (GCLC)	OTESDI4D	GSH1_HUMAN	Decreases Expression	[7]
Glutamate--cysteine ligase regulatory subunit (GCLM)	OT6CP234	GSH0_HUMAN	Decreases Expression	[7]
Rho GDP-dissociation inhibitor 1 (ARHGDIA)	OTEXWJDO	GDIR1_HUMAN	Increases Expression	[7]
Aldo-keto reductase family 1 member C2 (AKR1C2)	OTQ2XMO3	AK1C2_HUMAN	Decreases Expression	[7]
Myc-associated zinc finger protein (MAZ)	OTEHKN1M	MAZ_HUMAN	Increases Expression	[7]
Tropomyosin alpha-4 chain (TPM4)	OTN4YLYR	TPM4_HUMAN	Increases Expression	[7]
Transgelin (TAGLN)	OTAEZ0KP	TAGL_HUMAN	Increases Expression	[7]
1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1)	OTG2T749	CP24A_HUMAN	Decreases Expression	[7]
Prostaglandin reductase 1 (PTGR1)	OTMAR351	PTGR1_HUMAN	Decreases Expression	[7]
Ankyrin repeat domain-containing protein 1 (ANKRD1)	OTHJ7JV9	ANKR1_HUMAN	Increases Expression	[7]
Na(+)/H(+) exchange regulatory cofactor NHE-RF2 (NHERF2)	OTRHB9SR	NHRF2_HUMAN	Increases Expression	[7]
Carbonic anhydrase 9 (CA9)	OTNA51XT	CAH9_HUMAN	Increases Expression	[7]
Dual specificity protein phosphatase 7 (DUSP7)	OT6Z5AHP	DUS7_HUMAN	Increases Expression	[7]
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3)	OT25JBA3	F263_HUMAN	Increases Expression	[7]
Filamin A-interacting protein 1-like (FILIP1L)	OTPY8IMS	FIL1L_HUMAN	Increases Expression	[7]
Angiomotin (AMOT)	OTWHDG9B	AMOT_HUMAN	Increases Expression	[7]
Glycerol-3-phosphate acyltransferase 3 (GPAT3)	OTJUGPK0	GPAT3_HUMAN	Decreases Expression	[7]
Cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3)	OTDMU3GP	CR3L3_HUMAN	Decreases Expression	[7]
Leukocyte-associated immunoglobulin-like receptor 2 (LAIR2)	OTKCADXC	LAIR2_HUMAN	Decreases Expression	[7]
Sterile alpha motif domain-containing protein 1 (SAMD1)	OT2LK4JW	SAMD1_HUMAN	Increases Expression	[7]
Lipocalin-15 (LCN15)	OT9YXMIL	LCN15_HUMAN	Increases Expression	[7]
Protein MTSS 2 (MTSS2)	OTKMNSBF	MTSS2_HUMAN	Increases Expression	[7]
Carbohydrate sulfotransferase 15 (CHST15)	OTNTM2SP	CHSTF_HUMAN	Increases Expression	[7]
Solute carrier family 22 member 15 (SLC22A15)	OT60WAAI	S22AF_HUMAN	Decreases Expression	[7]
BPI fold-containing family B member 2 (BPIFB2)	OTXWTWQ9	BPIB2_HUMAN	Increases Expression	[7]
Arrestin domain-containing protein 4 (ARRDC4)	OTINJ0FX	ARRD4_HUMAN	Decreases Expression	[7]
Phospholipid phosphatase-related protein type 1 (PLPPR1)	OT4A560N	PLPR1_HUMAN	Increases Expression	[7]
Jun dimerization protein 2 (JDP2)	OTW35WKX	JDP2_HUMAN	Decreases Expression	[7]
Aquaporin-3 (AQP3)	OT2J7JPD	AQP3_HUMAN	Decreases Expression	[7]
Arrestin domain-containing protein 3 (ARRDC3)	OTAKW7R9	ARRD3_HUMAN	Decreases Expression	[7]
Small integral membrane protein 14 (SMIM14)	OT47IF19	SIM14_HUMAN	Decreases Expression	[7]
Sulfiredoxin-1 (SRXN1)	OTYDBO4L	SRXN1_HUMAN	Decreases Expression	[7]
Homeobox protein Hox-D1 (HOXD1)	OTN4V9ZF	HXD1_HUMAN	Increases Expression	[7]
Regulator of cell cycle RGCC (RGCC)	OTYJMLWM	RGCC_HUMAN	Increases Expression	[7]
Serine/threonine-protein kinase Sgk2 (SGK2)	OTCTVSHF	SGK2_HUMAN	Decreases Expression	[7]
Endothelial cell-specific molecule 1 (ESM1)	OT331Y8V	ESM1_HUMAN	Decreases Expression	[7]
]-phosphatase 2, mitochondrial (PDP2)	OTADNMGK	PDP2_HUMAN	Increases Expression	[7]
Cell cycle progression protein 1 (CCPG1)	OT0IHDKL	CCPG1_HUMAN	Decreases Expression	[7]
Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14)	OTN51IPT	S6A14_HUMAN	Increases Expression	[7]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Decreases Expression	[7]
Proliferation-associated protein 2G4 (PA2G4)	OT7IG7HT	PA2G4_HUMAN	Increases Expression	[7]
Pirin (PIR)	OT8ALXHU	PIR_HUMAN	Increases Expression	[19]
Tripartite motif-containing protein 16 (TRIM16)	OTLRXYOZ	TRI16_HUMAN	Increases Expression	[19]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Increases Expression	[19]
Liver carboxylesterase 1 (CES1)	OT9L0LR8	EST1_HUMAN	Increases Expression	[19]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[20]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[20]
Tumor necrosis factor receptor superfamily member 5 (CD40)	OT5YU2XB	TNR5_HUMAN	Increases Expression	[20]
Excitatory amino acid transporter 2 (SLC1A2)	OTEP3QGN	EAA2_HUMAN	Increases Expression	[21]
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Increases Transport	[22]

Indication(s) of Azithromycin

Disease Entry	ICD 11	Status	REF
Acute gonococcal cervicitis	N.A.	Approved	[4]
Bronchitis	CA20	Approved	[5]
Chancroid	N.A.	Approved	[4]
Mycoplasma pneumoniae pneumonia	N.A.	Approved	[4]
Staphylococcus aureus infection	N.A.	Approved	[4]
Streptococcal pneumonia	N.A.	Approved	[4]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]
Pneumonia caused by chlamydia	N.A.	Investigative	[4]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Preterm Premature Rupture of Membranes (PPROM)	DC79T9J	N. A.	Phase 3	[23]
Preterm Pre-labor Rupture of Membranes	DCTXX6Y	N. A.	Phase 1	[1]

References

• [1] ClinicalTrials.gov (NCT04202380) Azithromycin for Preterm Pre-labor Rupture of Membranes
• [2] Ampicillin FDA Label
• [3] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 061936.
• [4] Azithromycin FDA Label
• [5] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 065511.
• [6] ClinicalTrials.gov (NCT04332107) Azithromycin for COVID-19 Treatment in Outpatients Nationwide. U.S. National Institutes of Health.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] Effects of amino acid alterations in penicillin-binding proteins (PBPs) 1a, 2b, and 2x on PBP affinities of penicillin, ampicillin, amoxicillin, cefditoren, cefuroxime, cefprozil, and cefaclor in 18 clinical isolates of penicillin-susceptible, -intermediate, and -resistant pneumococci. Antimicrob Agents Chemother. 2002 May;46(5):1273-80.
• [9] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [10] Several hPepT1-transported drugs are substrates of the Escherichia coli proton-coupled oligopeptide transporter YdgR. Res Microbiol. 2017 Jun;168(5):443-449.
• [11] Transport characteristics of a novel peptide transporter 1 substrate, antihypotensive drug midodrine, and its amino acid derivatives. J Pharmacol Exp Ther. 2006 Jul;318(1):455-60.
• [12] A novel quorum-quenching N-acylhomoserine lactone acylase from Acidovorax sp. strain MR-S7 mediates antibiotic resistance. Appl Environ Microbiol. 2017 Jun 16;83(13). pii: e00080-17.
• [13] Purification and characterization of a new beta-lactamase from Bacteroides uniformis. Antimicrob Agents Chemother. 1995 Jul;39(7):1458-61.
• [14] Characterization of the AmpC beta-Lactamase from Burkholderia multivorans. Antimicrob Agents Chemother. 2018 Sep 24;62(10). pii: e01140-18.
• [15] Beta-lactamase production and antimicrobial susceptibility of subgingival bacteria from refractory periodontitis. Oral Microbiol Immunol. 2004 Oct;19(5):303-8.
• [16] Beta-lactamase expression in Plesiomonas shigelloides. J Antimicrob Chemother. 2000 Jun;45(6):877-80.
• [17] Drug-resistant genes carried by Acinetobacter baumanii isolated from patients with lower respiratory tract infection. Chin Med J (Engl). 2010 Sep;123(18):2571-5.
• [18] Effects of some antibiotics on paraoxonase from human serum in vitro and from mouse serum and liver in vivo. Biol Pharm Bull. 2006 Aug;29(8):1559-63.
• [19] Evaluation of the sensitizing potential of antibiotics in vitro using the human cell lines THP-1 and MUTZ-LC and primary monocyte-derived dendritic cells. Toxicol Appl Pharmacol. 2012 Aug 1;262(3):283-92.
• [20] Systemic drugs inducing non-immediate cutaneous adverse reactions and contact sensitizers evoke similar responses in THP-1 cells. J Appl Toxicol. 2015 Apr;35(4):398-406. doi: 10.1002/jat.3033. Epub 2014 Aug 4.
• [21] Translational control of glial glutamate transporter EAAT2 expression. J Biol Chem. 2007 Jan 19;282(3):1727-37. doi: 10.1074/jbc.M609822200. Epub 2006 Nov 30.
• [22] Multichannel liquid chromatography-tandem mass spectrometry cocktail method for comprehensive substrate characterization of multidrug resistance-associated protein 4 transporter. Pharm Res. 2007 Dec;24(12):2281-96.
• [23] ClinicalTrials.gov (NCT03060473) Treatment of ppROM With Erythromycin vs. Azithromycin Trial