Target Validation Information
TTD ID	T72657
Target Name	Staphylococcus 30S ribosomal subunit (Stap-coc pbp2)
Type of Target	Successful
Drug Potency against Target	Demeclocycline	Drug Info	IC50 = 20 ng/mL	[12]
	Framycetin	Drug Info	Ki = 7.0 nM	[8]
	Kanamycin	Drug Info	IC50 = 1~C8 g/ml	[1]
	Minocycline	Drug Info	IC55 = 1 nM	[6]
	Netilmicin	Drug Info	IC50 = 64000 nM	[7]
	Oxytetracycline	Drug Info	IC50 = 40 ng/mL	[12]
	Paromomycin	Drug Info	IC50 = 6.0 mcg/ml	[2]
	Streptomycin	Drug Info	MIC = 1~8 ug/ml	[9]
	Tetracycline	Drug Info	IC50 = 1000 ng/mL	[12]
	Tigecycline	Drug Info	IC50 = 160 nM	[10]
Action against Disease Model	Amikacin	Drug Info	The 50% inhibitory concentrations (IC50) of benzylpenicillin, streptomycin, sisomicin, gentamicin, tobramycin, kanamycin, amikacin, and butirosin were determined for 58 clinicalisolates of Streptococcus faecalis, 28 of which were recovered from cultures of blood samples from patients with endocarditis. The IC50 of streptomycin was less than 100 micro ng/mL for 42 strains, 192-10,000 micro ng/mL for eight, and larger than or equal to 10,000 micron/ml for eight. One isolate that was highly resistant to streptomycin was also highly resistant to kanamycin and butirosin. Extraordinarily high resistance to the other aminoglycosides was not observed. The bactericidal effects of combinations of penicillin and aminoglycosides were studied in 20 strains of S. faecalis that represented different levels of resistance to streptomycin. Significant enhancement of the effect of the combination of penicillin and streptomycin was found only in strains with an IC50 of smaller thanor equal to 190 micro ng/mL. Combinations of penicillin and sisomicin, gentamicin, or tobramycin were effective even against strains that were highly resistant to streptomycin and kanamycin.	[13]
	Framycetin	Drug Info	A n uMber of different antibiotics that prevent translation by binding to the 50S ribosomal subunit of bacterial cells have recently been shown to also prevent assembly of this subunit. Antibacterial agents affecting 30S particle activities have not been examined extensively for effects on small subunit formation. The aminoglycoside antibiotics paromomycin and neomycin bind specifically to the 30S ribosomal subunit and inhibit translation. These drugs were examined in Staphylococcus aureus cells to see whether they had a second inhibitory effect on 30S particle assembly.A 3H-uridine pulse and chase assay was used to examine the kinetics of subunit synthesis in the presence and absence of each antibiotic. 30S subunit formation was inhibited by both compounds. At 3 microg/mL each antibiotic reduced the rate of 30S formation by 80% compared with control cells. Both antibiotics showed a concentration-dependent inhibition of particle formation, with a lesser effect on 50S particle formation. For neomycin, the IC50 for 30S particle formation was equal to the IC50 for inhibition of translation. Both antibiotics reduced the viable cell n uMber with an IC50 of 2 microg/mL. They also inhibited protein synthesis in the cells with different IC50 values (2.5 and 1.25 microg/mL). This is the second demonstration of 30S ribosomal subunit-specific antibiotics that prevent assembly of the small subunit.	[3]
	Framycetin	Drug Info	IC50 on luciferase synthesis in Mycobacteri uM smegmatis: 40 nM	[7]
	Kanamycin	Drug Info	IC50 on luciferase synthesis in Mycobacteri uM smegmatis: 50 nM	[7]
	Lymecycline	Drug Info	Comparisons of the inhibitory activities of different tetracyclines have been reported for Plasmodi uM falcipar uM but no other parasites. The in vitro response of the intestinal parasite Giardia lamblia to six tetracyclines in current use was determined. In addition, the experimental drug thiacycline (EMD 33,330) was evaluated. Three groups were discerned, with representative 50 and 90% inhibitory concentrations of, respectively, 36 and 130 (tetracycline), 6.4 and 22 (doxycycline), and 1.8 and 3.4 (thiacycline) micrograms/ml. These dramatic differences in activity correlate with increased lipophilicity.	[11]
	Netilmicin	Drug Info	IC50 on luciferase synthesis in Mycobacteri uM smegmatis: 50 nM	[7]
	Paromomycin	Drug Info	IC50 on luciferase synthesis in Mycobacteri uM smegmatis: 30 nM	[7]
	Rolitetracycline	Drug Info	Limited structural information of drug targets, cellular toxicity possessed by lead compounds, and large amounts of potential leads are the major issues facing the design-oriented approach of discovering new leads. In an attempt to tackle these issues, we have developed a process of virtual screening based on the observation that conformational rearrangements of the dengue virus envelope protein are essential for the mediation of viral entry into host cells via membrane fusion. Screening was based solely on the structural information of the Dengue virus envelope protein and was focused on a target site that is pres uMably important for the conformational rearrangements necessary for viral entry. To circ uMvent the issue of lead compound toxicity, we performed screening based on molecular docking using structural databases of medical compounds. To enhance the identification of hits, we further categorized and selected candidates according to their novel structuralcharacteristics. Finally, the selected candidates were subjected to a biological validation assay to assess inhibition of Dengue virus propagation in mammalian host cells using a plaque formation assay. Among the 10 compounds examined, rolitetracycline and doxycycline significantly inhibited plaque formation, demonstrating their inhibitory effect on dengue virus propagation. Both compounds were tetracycline derivatives with IC(50)s estimated to be 67.1 microM and 55.6 microM, respectively. Their docked conformations displayed common hydrophobic interactions with critical residues that affected membrane fusion during viral entry. These interactions will therefore position the tetracyclic ring moieties of both inhibitors to bind firmly to the target and, subsequently, disrupt conformationalrearrangement and block viral entry. This process can be applied to other drug targets in which conformational rearrangement is critical to function.	[5]
	Spectinomycin	Drug Info	The in vitro and in vivo effects of selected natural flavonoids (flavone, flavanone, tangeretin, quercetin, chrysin) on the microsome-catalysed binding of [3H]benzo[a]pyrene to calf thymus DNA were investigated and compared with those of two synthetic flavonoids, 7,8-benzoflavone and 5,6-benzoflavone. In vitro addition of these flavonoids (0.1 mM) to an incubation system containing hepatic microsomes prepared from Aroclor 1254-pretreated rats strongly inhibited BaP-DNA adduct formation (72-89%). The incubation of BaP with hepatic microsomes prepared from animals fed 0.3%quercetin, tangeretin and 7,8-benzoflavone for 2 weeks also resulted in less effective binding of BaP metabolites to added DNA, than with microsomes from untreated rats. Other tested compounds, chrysin, flavone, flavanone and 5,6-benzoflavone showed no or little effect. The influence of flavonoid pretreatment on hepatic microsomal enzymes involved in BaP metabolism has also been examined. Aryl hydrocarbon hydroxylase activity was moderately increased (1.5-1.8-fold) in microsomes prepared from rats fed flavone, tangeretin, 7,8-benzoflavone and 5,6-benzo-flavone. Epoxide hydrolase activity was enhanced by 7,8-benzoflavone (1,6-fold), and by flavone and flavanone (5-fold). These results confirm that flavonoids, in vitro, are potent inhibitors of carcinogen-DNA binding. Oral administration of0.3% flavonoids alters the properties of liver microsomes, resulting in the decreased ability of BaP metabolites to bind DNA.	[4]
	Streptomycin	Drug Info	The in vitro and in vivo effects of selected natural flavonoids (flavone, flavanone, tangeretin, quercetin, chrysin) on the microsome-catalysed binding of [3H]benzo[a]pyrene to calf thymus DNA were investigated and compared with those of two synthetic flavonoids, 7,8-benzoflavone and 5,6-benzoflavone. In vitro addition of these flavonoids (0.1 mM) to an incubation system containing hepatic microsomes prepared from Aroclor 1254-pretreated rats strongly inhibited BaP-DNA adduct formation (72-89%). The incubation of BaP with hepatic microsomes prepared from animals fed 0.3%quercetin, tangeretin and 7,8-benzoflavone for 2 weeks also resulted in less effective binding of BaP metabolites to added DNA, than with microsomes from untreated rats. Other tested compounds, chrysin, flavone, flavanone and 5,6-benzoflavone showed no or little effect. The influence of flavonoid pretreatment on hepatic microsomal enzymes involved in BaP metabolism has also been examined. Aryl hydrocarbon hydroxylase activity was moderately increased (1.5-1.8-fold) in microsomes prepared from rats fed flavone, tangeretin, 7,8-benzoflavone and 5,6-benzo-flavone. Epoxide hydrolase activity was enhanced by 7,8-benzoflavone (1,6-fold), and by flavone and flavanone (5-fold). These results confirm that flavonoids, in vitro, are potent inhibitors of carcinogen-DNA binding. Oral administration of0.3% flavonoids alters the properties of liver microsomes, resulting in the decreased ability of BaP metabolites to bind DNA.	[4]
References
REF 1	The magic bullets and tuberculosis drug targets. Annu Rev Pharmacol Toxicol. 2005;45:529-64.
REF 2	Bacterial ribosomal subunit assembly is an antibiotic target. Curr Top Med Chem. 2003;3(9):929-47.
REF 3	Neomycin and paromomycin inhibit 30S ribosomal subunit assembly in Staphylococcus aureus. Curr Microbiol. 2003 Sep;47(3):237-43.
REF 4	Inhibition of microsome-mediated binding of benzo[a]pyrene to DNA by flavonoids either in vitro or after dietary administration to rats. Chem Biol Interact. 1992 Jun 15;83(1):65-71.
REF 5	Combinatorial computational approaches to identify tetracycline derivatives as flavivirus inhibitors. PLoS One. 2007 May 9;2(5):e428.
REF 6	Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov. 2007 Jun;6(6):480-98.
REF 7	Engineering the rRNA decoding site of eukaryotic cytosolic ribosomes in bacteria. Nucleic Acids Res. 2007;35(18):6086-93.
REF 8	Low molecular weight inhibitors of the protease anthrax lethal factor. Mini Rev Med Chem. 2008 Mar;8(3):290-306.
REF 9	New anti-tuberculosis drugs with novel mechanisms of action. Curr Med Chem. 2008;15(19):1956-67.
REF 10	In vitro activity of tigecycline in Plasmodium falciparum culture-adapted strains and clinical isolates from Gabon. Int J Antimicrob Agents. 2010 Jun;35(6):587-9.
REF 11	Tetracyclines as antiparasitic agents: lipophilic derivatives are highly active against Giardia lamblia in vitro. Antimicrob Agents Chemother. 1989 Dec;33(12):2144-5.
REF 12	In vitro susceptibilities of Ehrlichia risticii to eight antibiotics. Antimicrob Agents Chemother. 1988 Jul;32(7):986-91.
REF 13	Effect of combinations of penicillin and aminoglycosides on Streptococcus faecalis: a comparative study of seven aminoglycoside antibiotics. J Infect Dis. 1977 May;135(5):832-6.

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