Details of the Drug Combination

General Information of Drug Combination (ID: DCQ7OW0)

• Drug Combination Name: Gentamicin + Azithromycin
• Indication: Gonorrhoea; Status: Phase 1 [1]
• Component Drugs:
  Gentamicin (DMKINJO): Small molecular drug
  Azithromycin (DMS6UOE): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Gentamicin

Disease Entry	ICD 11	Status	REF
Bacteremia	1A73	Approved	[2]
Bacterial infection	1A00-1C4Z	Approved	[3]
Blepharoconjunctivitis	N.A.	Approved	[2]
Cholangitis	N.A.	Approved	[2]
Dacryocystitis	N.A.	Approved	[2]
Demodex blepharitis	1G07	Approved	[2]
Folliculitis	N.A.	Approved	[2]
Neonatal sepsis	N.A.	Approved	[2]
Paronychia	1F23.13	Approved	[2]
Peritonitis	N.A.	Approved	[2]
Pseudomonas aeruginosa infectious disease	N.A.	Approved	[2]

Gentamicin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial 30S ribosomal RNA (Bact 30S rRNA)	TTOVFH2	NOUNIPROTAC	Modulator	[9]

Gentamicin Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Aminoglycoside O-phosphotransferase (aphA6)	DEWPAJD	KKA6_ACIBA	Metabolism	[10]
Aminoglycoside phosphotransferase (aph-Ib)	DE5WGIM	A0A075C7U3_CAMJU	Metabolism	[11]
Kanamycin/gentamycin-resistance enzyme (aacA)	DECXWN8	J3S7E2_CAMCO	Metabolism	[11]
Endoglucanase Y (EGY)	DE2M583	A0A256VAC0_LACRE	Metabolism	[12]
Endoglucanase Y (EGY)	DE2AZTG	A0A256VAC0_LACRE	Metabolism	[12]
Aminoglycoside 6'-N-acetyltransferase (aacA)	DE48UAX	C5MQW3_KLEPO	Metabolism	[13]

Gentamicin Interacts with 53 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Alpha-L-iduronidase (IDUA)	OTTQQ7FN	IDUA_HUMAN	Increases Expression	[14]
Tripeptidyl-peptidase 1 (TPP1)	OT2LQ771	TPP1_HUMAN	Increases Expression	[15]
Exocyst complex component 3 (EXOC3)	OT8N3306	EXOC3_HUMAN	Increases Expression	[16]
Slit homolog 1 protein (SLIT1)	OT35RBNT	SLIT1_HUMAN	Decreases Expression	[8]
Coagulation factor VIII (F8)	OTH6XHDU	FA8_HUMAN	Increases Expression	[17]
Coagulation factor IX (F9)	OTT0CX3Q	FA9_HUMAN	Increases Expression	[17]
Cystatin-C (CST3)	OTNZ6AO4	CYTC_HUMAN	Increases Expression	[16]
Pro-epidermal growth factor (EGF)	OTANRJ0L	EGF_HUMAN	Decreases Expression	[16]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[18]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[16]
Intercellular adhesion molecule 1 (ICAM1)	OTTOIX77	ICAM1_HUMAN	Increases Expression	[16]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[7]
Heat shock 70 kDa protein 1A (HSPA1A)	OTKGIE76	HS71A_HUMAN	Increases Expression	[19]
Dystrophin (DMD)	OTD21T5J	DMD_HUMAN	Increases Expression	[20]
Xaa-Pro dipeptidase (PEPD)	OT3LFY7S	PEPD_HUMAN	Decreases Activity	[21]
Cystic fibrosis transmembrane conductance regulator (CFTR)	OT6B22QH	CFTR_HUMAN	Increases Activity	[22]
Aminopeptidase N (ANPEP)	OTP3WYFD	AMPN_HUMAN	Increases Secretion	[23]
Methylmalonyl-CoA mutase, mitochondrial (MMUT)	OTBBBV70	MUTA_HUMAN	Affects Expression	[24]
Growth arrest and DNA damage-inducible protein GADD45 alpha (GADD45A)	OTDRV63V	GA45A_HUMAN	Increases Expression	[7]
Endothelin receptor type B (EDNRB)	OTLLZV3P	EDNRB_HUMAN	Increases Expression	[8]
Insulin-like growth factor-binding protein 5 (IGFBP5)	OTRE5V0C	IBP5_HUMAN	Decreases Expression	[8]
HLA class I histocompatibility antigen, alpha chain F (HLA-F)	OT76CM19	HLAF_HUMAN	Increases Expression	[8]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[16]
Leukemia inhibitory factor receptor (LIFR)	OT36W9O5	LIFR_HUMAN	Decreases Degradation	[25]
ATP-sensitive inward rectifier potassium channel 1 (KCNJ1)	OTIXCRI6	KCNJ1_HUMAN	Increases Expression	[26]
Cytosolic purine 5'-nucleotidase (NT5C2)	OTJMF66Z	5NTC_HUMAN	Increases Expression	[8]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Expression	[16]
Potassium voltage-gated channel subfamily KQT member 4 (KCNQ4)	OT29B58J	KCNQ4_HUMAN	Decreases Expression	[8]
Beta-2-microglobulin (B2M)	OTDWN6NX	B2MG_HUMAN	Increases Expression	[27]
Neutrophil gelatinase-associated lipocalin (LCN2)	OTSB42BR	NGAL_HUMAN	Decreases Secretion	[28]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[16]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Increases Expression	[29]
Polycystin-2 (PKD2)	OTIXBU8H	PKD2_HUMAN	Increases Expression	[30]
Runt-related transcription factor 3 (RUNX3)	OTITK1XD	RUNX3_HUMAN	Decreases Expression	[8]
Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)	OTXEE550	APR_HUMAN	Increases Expression	[7]
Interleukin-18 (IL18)	OTBB2A8O	IL18_HUMAN	Decreases Expression	[16]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Expression	[16]
Partitioning defective 3 homolog (PARD3)	OTH5BPLO	PARD3_HUMAN	Decreases Expression	[8]
GATOR1 complex protein NPRL2 (NPRL2)	OTOB10MO	NPRL2_HUMAN	Decreases Expression	[8]
Hepatitis A virus cellular receptor 1 (HAVCR1)	OT184CRZ	HAVR1_HUMAN	Increases Expression	[16]
Rho guanine nucleotide exchange factor 26 (ARHGEF26)	OTX0U8PX	ARHGQ_HUMAN	Increases Expression	[8]
G-protein coupled receptor 20 (GPR20)	OTPCR8F7	GPR20_HUMAN	Increases Expression	[8]
Polyadenylate-binding protein-interacting protein 1 (PAIP1)	OTL2F5T5	PAIP1_HUMAN	Decreases Expression	[8]
Large subunit GTPase 1 homolog (LSG1)	OTDAXJ9L	LSG1_HUMAN	Decreases Expression	[8]
Glyoxalase domain-containing protein 4 (GLOD4)	OTBJKFXA	GLOD4_HUMAN	Decreases Expression	[8]
DNA-directed DNA/RNA polymerase mu (POLM)	OT0SRIP4	DPOLM_HUMAN	Increases Expression	[8]
Ubiquitin-like-conjugating enzyme ATG3 (ATG3)	OT28VBVK	ATG3_HUMAN	Decreases Expression	[8]
Phospholipase A2 (PLA2G1B)	OT1GG9FK	PA21B_HUMAN	Increases ADR	[31]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1)	OT9HYT7A	PLCB1_HUMAN	Increases ADR	[31]
Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1)	OTCJ458Q	AT1A1_HUMAN	Increases ADR	[31]
Solute carrier family 22 member 2 (SLC22A2)	OTGFK1AL	S22A2_HUMAN	Increases Transport	[32]
Lysosomal Pro-X carboxypeptidase (PRCP)	OTIUY91L	PCP_HUMAN	Increases ADR	[31]
Dipeptidyl aminopeptidase-like protein 6 (DPP6)	OTWW3H0K	DPP6_HUMAN	Increases ADR	[31]

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]

References

• [1] ClinicalTrials.gov (NCT00926796) Efficacy of Combination Therapies for Gonorrhea Treatment
• [2] Gentamicin FDA Label
• [3] 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: 2427).
• [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] A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro. J Am Soc Nephrol. 2016 Apr;27(4):1015-28. doi: 10.1681/ASN.2015010060. Epub 2015 Aug 10.
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• [9] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [10] Relationship between antimicrobial resistance and aminoglycoside-modifying enzyme gene expressions in Acinetobacter baumannii. Chin Med J (Engl). 2005 Jan 20;118(2):141-5.
• [11] Cloning and expression of novel aminoglycoside phosphotransferase genes from Campylobacter and their role in the resistance to six aminoglycosides. Antimicrob Agents Chemother. 2017 Dec 21;62(1). pii: e01682-17.
• [12] Expression of Clostridium thermocellum endoglucanase gene in Lactobacillus gasseri and Lactobacillus johnsonii and characterization of the genetically modified probiotic lactobacilli. Curr Microbiol. 2000 Apr;40(4):257-63.
• [13] Detection of multidrug-resistant Enterobacteriaceae isolated from river waters flowing to the Guanabara Bay and from clinical samples of hospitals in Rio de Janeiro, Brazil. Biomedica. 2019 May 1;39(s1):135-149.
• [14] Alpha-L-iduronidase premature stop codons and potential read-through in mucopolysaccharidosis type I patients. J Mol Biol. 2004 Apr 30;338(3):453-62.
• [15] Aminoglycoside-mediated suppression of nonsense mutations in late infantile neuronal ceroid lipofuscinosis. Eur J Paediatr Neurol. 2001;5 Suppl A:57-62. doi: 10.1053/ejpn.2000.0436.
• [16] In vitro evaluation of biomarkers of nephrotoxicity through gene expression using gentamicin. J Biochem Mol Toxicol. 2018 Sep;32(9):e22189. doi: 10.1002/jbt.22189. Epub 2018 Jul 10.
• [17] Aminoglycoside suppression of nonsense mutations in severe hemophilia. Blood. 2005 Nov 1;106(9):3043-8. doi: 10.1182/blood-2005-03-1307. Epub 2005 Jul 28.
• [18] Gentamicin suppresses endotoxin-driven TNF-alpha production in human and mouse proximal tubule cells. Am J Physiol Renal Physiol. 2007 Oct;293(4):F1373-80. doi: 10.1152/ajprenal.00333.2007. Epub 2007 Aug 15.
• [19] Increased expression of heat shock protein (HSP)72 in a human proximal tubular cell line (HK-2) with gentamicin-induced injury. J Toxicol Sci. 2006 Feb;31(1):61-70. doi: 10.2131/jts.31.61.
• [20] Gentamicin administration in Duchenne patients with premature stop codon. Preliminary results. Acta Myol. 2003 May;22(1):15-21.
• [21] Melanin potentiates gentamicin-induced inhibition of collagen biosynthesis in human skin fibroblasts. Eur J Pharmacol. 2002 Jun 20;446(1-3):7-13. doi: 10.1016/s0014-2999(02)01793-4.
• [22] Correction of CFTR malfunction and stimulation of Ca-activated Cl channels restore HCO3- secretion in cystic fibrosis bile ductular cells. Hepatology. 2002 Jan;35(1):95-104. doi: 10.1053/jhep.2002.30423.
• [23] Investigations on the potential nephrotoxicity of cefazedone and gentamicin and of their combination, in comparison with the combination of cefazolin and cephalothin with gentamicin. Arzneimittelforschung. 1979;29(2a):449-52.
• [24] Stop codon read-through of a methylmalonic aciduria mutation. Mol Genet Metab. 2009 Aug;97(4):244-9. doi: 10.1016/j.ymgme.2009.04.004. Epub 2009 Apr 12.
• [25] In vitro readthrough of termination codons by gentamycin in the Stve-Wiedemann Syndrome. Eur J Hum Genet. 2010 Jan;18(1):130-2. doi: 10.1038/ejhg.2009.122.
• [26] Classification and rescue of ROMK mutations underlying hyperprostaglandin E syndrome/antenatal Bartter syndrome. Kidney Int. 2003 Sep;64(3):923-32. doi: 10.1046/j.1523-1755.2003.00153.x.
• [27] The absence of nephrotoxicity and differential nephrotoxicity between tobramycin and gentamicin. South Med J. 1990 Oct;83(10):1149-52. doi: 10.1097/00007611-199010000-00008.
• [28] Neutrophil gelatinase-associated lipocalin production negatively correlates with HK-2 cell impairment: Evaluation of NGAL as a marker of toxicity in HK-2 cells. Toxicol In Vitro. 2017 Mar;39:52-57. doi: 10.1016/j.tiv.2016.11.012. Epub 2016 Nov 22.
• [29] Correction of ATM gene function by aminoglycoside-induced read-through of premature termination codons. Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15676-81. doi: 10.1073/pnas.0405155101. Epub 2004 Oct 21.
• [30] Deficiency of polycystin-2 reduces Ca2+ channel activity and cell proliferation in ADPKD lymphoblastoid cells. FASEB J. 2004 May;18(7):884-6. doi: 10.1096/fj.03-0687fje. Epub 2004 Mar 4.
• [31] 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.
• [32] Organic Cation Transporter 2 Overexpression May Confer an Increased Risk of Gentamicin-Induced Nephrotoxicity. Antimicrob Agents Chemother. 2016 Aug 22;60(9):5573-80. doi: 10.1128/AAC.00907-16. Print 2016 Sep.