Details of the Drug Combination

General Information of Drug Combination (ID: DC69BGG)

• Drug Combination Name: Ceftazidime + Tobramycin
• Indication: Cystic Fibrosis; Status: Phase 1 [1]
• Component Drugs:
  Ceftazidime (DM41GRA): Small molecular drug
  Tobramycin (DMUI0CH): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ceftazidime

Disease Entry	ICD 11	Status	REF
Bacteremia	1A73	Approved	[2]
Bacterial infection	1A00-1C4Z	Approved	[3]
Endometritis	N.A.	Approved	[2]
Meningococcal meningitis	N.A.	Approved	[2]
Peritonitis	N.A.	Approved	[2]
Staphylococcal pneumonia	N.A.	Approved	[2]
Staphylococcus aureus infection	N.A.	Approved	[2]
Pelvic inflammatory disease	GA05	Investigative	[2]

Ceftazidime 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	[6]

Ceftazidime Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Dihydrofolate reductase (DHFR)	OT3DVIGM	DYR_HUMAN	Decreases Activity	[7]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Decreases Activity	[8]
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Increases Transport	[9]

Indication(s) of Tobramycin

Disease Entry	ICD 11	Status	REF
Bacteremia	1A73	Approved	[4]
Bacterial infection	1A00-1C4Z	Approved	[5]
Blepharoconjunctivitis	N.A.	Approved	[4]
Corneal abrasion	NA06.4	Approved	[4]
Dacryocystitis	N.A.	Approved	[4]
Demodex blepharitis	1G07	Approved	[4]
Neonatal sepsis	N.A.	Approved	[4]
Peritonitis	N.A.	Approved	[4]
Rosacea	ED90.0	Approved	[4]
Staphylococcal pneumonia	N.A.	Approved	[4]
Staphylococcus aureus infection	N.A.	Approved	[4]

Tobramycin 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	[11]

Tobramycin Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
RNA cytidine acetyltransferase (hALP)	DEZV4AP	NAT10_HUMAN	Metabolism	[12]
Aminoglycoside O-phosphotransferase (aphA6)	DEWPAJD	KKA6_ACIBA	Metabolism	[13]
Aminoglycoside phosphotransferase (aph-Ib)	DE5WGIM	A0A075C7U3_CAMJU	Metabolism	[14]
Kanamycin/gentamycin-resistance enzyme (aacA)	DECXWN8	J3S7E2_CAMCO	Metabolism	[14]
Aminoglycoside N-acetyltransferase (aacC2)	DEJADS9	AAC6_ACIBA	Metabolism	[13]

Tobramycin Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[10]
Growth arrest and DNA damage-inducible protein GADD45 alpha (GADD45A)	OTDRV63V	GA45A_HUMAN	Increases Expression	[10]
Beta-2-microglobulin (B2M)	OTDWN6NX	B2MG_HUMAN	Increases Expression	[15]
Survival motor neuron protein (SMN2)	OT54RLO1	SMN_HUMAN	Increases Expression	[16]
Phospholipase A2 (PLA2G1B)	OT1GG9FK	PA21B_HUMAN	Increases ADR	[17]
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 (PLCB1)	OT9HYT7A	PLCB1_HUMAN	Increases ADR	[17]
Lysozyme C (LYZ)	OTD7H0G6	LYSC_HUMAN	Increases ADR	[17]
L-lactate dehydrogenase A chain (LDHA)	OTN7K4XB	LDHA_HUMAN	Increases ADR	[17]
Beta-hexosaminidase (nag1)	OTQCIZOD	P87258_TRIHA	Increases ADR	[17]

References

• [1] ClinicalTrials.gov (NCT02526004) Cystic Fibrosis Microbiome-determined Antibiotic Therapy Trial in Exacerbations: Results Stratified
• [2] Ceftazidime FDA Label
• [3] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [4] Tobramycin FDA Label
• [5] How many modes of action should an antibiotic have Curr Opin Pharmacol. 2008 Oct;8(5):564-73.
• [6] New and emerging treatment of Staphylococcus aureus infections in the hospital setting. Clin Microbiol Infect. 2008 Apr;14 Suppl 3:32-41.
• [7] Investigation of the effects of some drugs and phenolic compounds on human dihydrofolate reductase activity. J Biochem Mol Toxicol. 2015 Mar;29(3):135-9.
• [8] A Gene Expression Biomarker Predicts Heat Shock Factor 1 Activation in a Gene Expression Compendium. Chem Res Toxicol. 2021 Jul 19;34(7):1721-1737. doi: 10.1021/acs.chemrestox.0c00510. Epub 2021 Jun 25.
• [9] 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.
• [10] 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.
• [11] Mechanism of action of aminoglycoside antibiotics.Binding studies of tobramycin and its 6'-N-acetyl derivative to the bacterial ribosome and its subunits.Eur J Biochem.1979 Dec;102(1):73-81.
• [12] Genetic analysis of bacterial acetyltransferases: identification of amino acids determining the specificities of the aminoglycoside 6'-N-acetyltransferase Ib and IIa proteins. J Bacteriol. 1992 May;174(10):3196-203.
• [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] 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.
• [15] 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.
• [16] Translational readthrough by the aminoglycoside geneticin (G418) modulates SMN stability in vitro and improves motor function in SMA mice in vivo. Hum Mol Genet. 2009 Apr 1;18(7):1310-22. doi: 10.1093/hmg/ddp030. Epub 2009 Jan 15.
• [17] 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.