Novobiocin
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| Novobiocin
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| Systematic (IUPAC) name | |
| 4-Hydroxy-3-[4-hydroxy-3-(3-methylbut-2-enyl)benzamido]-8-methylcoumarin-7-yl 3-O-carbamoyl-5,5-di-C-methyl-α-l-lyxofuranoside | |
| Identifiers | |
| CAS number | |
| ATC code | ? |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C31H36N2O11 |
| Mol. mass | 612.624 |
| Pharmacokinetic data | |
| Bioavailability | negligible oral bioavailability |
| Metabolism | excreted unchanged |
| Half life | 6 hours |
| Excretion | renal |
| Therapeutic considerations | |
| Pregnancy cat. |
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| Legal status |
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| Routes | intravenous |
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Novobiocin is an aminocoumarin antibiotic that was produced by the actinomycete Streptomyces niveus, which has recently been identified as a subjective synonym for S. spheroides[1] a member of the order Actinobacteria . Other aminocoumarin antibiotics include clorobiocin and coumermycin A1.[2] Novobiocin was first reported in the middle of 1950s (called then streptonivicin).[3][4]
Mechanism of action
The molecular basis of action of novobiocin, and other related drugs clorobiocin and coumermycin A1 has been examined.[2][5][6][7][8] Aminocoumarins are very potent inhibitors of bacterial DNA gyrase and work by targeting the GyrB subunit of the enzyme involved in energy tranduction. Novobiocin as well as the other aminocoumarin antibiotics act as competitive inhibitors of the ATPase reaction catalysed by GyrB. The potency of novobiocin is considerably higher than that of the fluoroquinolones that also target DNA gyrase, but at a different site on the enzyme. The GyrA subunit is involved in the DNA nicking and ligation activity.
Structure
Novobiocin is an aromatic ether compound. Novobiocin may be divided up into three entities; a benzoic acid derivative, a coumarin residue, and the sugar novobiose.[5]. X-ray crytallographic studies have found that the drug-receptor complex of Novobiocin and DNA Gyrase shows that ATP and Novobiocin have overlapping binding sites on the gyrase molecule.[9] The overlap of the coumarin and ATP-binding sites is consistent with aminocoumarins being competitive inhibitors of the ATPase activity.[10]
Structure Activity Relationship
In structure activity relationship experiments it was found that removal of the carbamoyl group located on the novobiose sugar lead to a dramatic decrease in inhibitory activity of novobiocin. [10]
Clinical Use
Novobiocin was licenced for clinical use under the tradename Albamycin® (Pharmacia And Upjohn) in the 1960s. Its efficacy has been demonstrated in preclinical and clinical trials.[11][12] It has since been withdrawn from the market.[13] Novobiocin is effective antistaphylococcal agent used in the treatment of MRSA[14]. It is also active against Staphylococcus epidermidis and may be used to differentiate from the other coagulase-negative Staphylococcus saprophyticus, which is resistant to novobiocin, in culture.
References
- ↑ Lanoot, B., M. Vancanneyt, I. Cleenwerck, L. Wang, W. Li, Z. Liu, and J. Swings. 2002. The search for synonyms among streptomycetes by with SDS-PAGE of whole-cell proteins. Emendation of the species Streptomyces aurantiacus, Streptomyces cacaoi subsp. cacaoi, Streptomyces caeruleus and Streptomyces violaceus. Int. J. Syst. Evol. Microbiol. 52:823-829.
- ↑ 2.0 2.1 Alessandra da Silva Eustáquio (2004) Biosynthesis of aminocoumarin antibiotics in Streptomyces: Generation of structural analogues by genetic engineering and insights into the regulation of antibiotic production. DISSERTATION
- ↑ Hoeksema, H., Johnson, J. L., and Hinman, J. W. (1955). Structural studies on streptonivicin, a new antibiotic. J Am Chem Soc, 77, 6710-6711.
- ↑ Smith, C. G., Dietz, A., Sokolski, W. T., and Savage, G. M. (1956). Streptonivicin, a new antibiotic. I. Discovery and biologic studies. Anitbiotics & Chemotherapy, 6, 135- 142.
- ↑ 5.0 5.1 Maxwell, A. (1993). The interaction between coumarin drugs and DNA gyrase. Mol Microbiol, 9, 681-686.
- ↑ Maxwell, A. (1999). DNA gyrase as a drug target. Biochem Soc Trans, 27, 48-53.
- ↑ Lewis, R. J., Tsai, F. T. F., and Wigley, D. B. (1996). Molecular mechanisms of drug inhibition of DNA gyrase. Bioessays, 18, 661-671.
- ↑ Maxwell, A., and Lawson, D. M. (2003). The ATP-binding site of type II topoisomerases as a target for antibacterial drugs. Curr Top Med Chem, 3, 283-303.
- ↑ F.T.F. Tsai, O.M. Singh, T.Skarzynski, A.J. Wonacott, S. Weston, A. Tucker, R.A. Pauptit, A.L. Breeze, J.P. Poyser, R. O'Brien et al., The high-resolution crystal structure of a 24-kDa gyrase B fragment from E. coli complexed with one of the most potent coumarin inhibitors, clorobiocin. Proteins 28 (1997), pp. 41–52
- ↑ 10.0 10.1 R.H. Flatman, A. Eustaquio, S. Li, L. Heide, and A. Maxwell (2006) Structure-Activity Relationships of Aminocoumarin-Type Gyrase and Topoisomerase IV Inhibitors Obtained by Combinatorial Biosynthesis Antimicrob Agents Chemother. 50(4): 1136–1142.
- ↑ Raad, I., Darouiche, R., Hachem, R., Sacilowski, M., and Bodey, G. P. (1995). Antibiotics and prevention of microbial colonization of catheters. Antimicrob Agents Chemother, 39, 2397-2400.
- ↑ Raad, I. I., Hachem, R. Y., Abi-Said, D., Rolston, K. V. I., Whimbey, E., Buzaid, A.C., and Legha, S. (1998). A prospective crossover randomized trial of novobiocinand rifampin prophylaxis for the prevention of intravascular catheter infections in cancer patients treated with interleukin-2. Cancer, 82, 403-411.
- ↑ http://fda-drugs.legalview.com/legal-issue/albamycin/
- ↑ T.J. Walsh et al.(1993) Randomized Double-Blinded Trial of Rifampin with Either Novobiocin or Trimethoprim-Sulfamethoxazole against Methicillin-Resistant Staphylococcus aureus Colonization: Prevention of Antimicrobial Resistance and Effect of Host Factors on Outcome. Antimicrobial agents and chemotherapy Vol 37 No 6 p. 1334-1342
Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
