Novobiocin: Difference between revisions

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==Overview==
==Overview==


'''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''<ref> 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.</ref> a member of the order [[Actinobacteria]] . Other aminocoumarin antibiotics include clorobiocin and coumermycin A1.<ref name=E>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</ref> Novobiocin was first reported in the middle of 1950s (called then streptonivicin).<ref>Hoeksema, H., Johnson, J. L., and Hinman, J. W. (1955). Structural studies on streptonivicin, a new antibiotic.'' J Am Chem Soc'', 77, 6710-6711.</ref><ref>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.</ref>
'''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'',<ref> 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.</ref> a member of the order [[Actinobacteria]]. Other aminocoumarin antibiotics include clorobiocin and coumermycin A1.<ref name=E>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</ref> Novobiocin was first reported in the middle of 1950s (called then streptonivicin).<ref>Hoeksema, H., Johnson, J. L., and Hinman, J. W. (1955). Structural studies on streptonivicin, a new antibiotic.'' J Am Chem Soc'', 77, 6710-6711.</ref><ref>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.</ref>


==Category==
==Category==

Revision as of 19:51, 6 January 2014

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: Novobiocin sodium; Streptonivicin

Overview

Novobiocin is an aminocoumarin antibiotic that was produced by the actinomycete Streptomyces niveus, which has recently been identified as a subjective synonym forS. 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]

Category

Aminocoumarin

US Brand Names

ALBAMYCIN® (DISCONTINUED)

Prescribing Information

Contraindications

Precautions

  • Liver dysfunction

Adverse Reactions

Cardiovascular Effects
  • Myocarditis
Myocarditis occurs infrequently with novobiocin.
Dermatologic Effects
Skin eruption and fever are the most frequent hypersensitivity phenomena. The incidence of the RASH is in about 12% of treated patients with an onset between the 6th and 12th day of treatment. The rash may appear erythematous, maculopapular, scarlatiniform, or urticarial.
YELLOW DISCOLORATION of the skin and plasma is the result of a circulating lipochrome pigment that is a degradation product of novobiocin.
The hemorrhagic nature of cutaneous lesions may indicate that novobiocin has a coumarin-like effect.
Hematologic Effects
  • Hematology finding
Hematologic effects, including LEUKOPENIA, HEMOLYTIC ANEMIA, AGRANULOCYTOSIS, PANCYTOPENIA, THROMBOCYTOPENIA, and EOSINOPHILIA have been reported in about 1% of treated patients.
Hepatic Effects
  • Jaundice
An increase in unconjugated bilirubin in plasma and jaundice have been reported in patients receiving therapeutic doses of novobiocin. Novobiocin inhibits glucuronyltransferase, which may lead to HYPERBILIRUBINEMIA if administered to newborn and young infants.
Immunologic Effects
  • Immune hypersensitivity reaction
Other reactions associated with the use of novobiocin include DRUG FEVER, SERUM SICKNESS, and STEVENS-JOHNSON SYNDROME.
Ophthalmic Effects
  • Eye / vision finding
YELLOWING OF THE SCLERAE may occur from circulation of a yellow lipochrome pigment that is a degradation product of novobiocin.
Respiratory Effects
  • Respiratory finding
Allergic PNEUMONITIS is uncommon with novobiocin.

Teratogenicity/Effects in Pregnancy

  • Fetal risk cannot be ruled out.
Available evidence is inconclusive or is inadequate for determining fetal risk when used in pregnant women or women of childbearing potential. Weigh the potential benefits of drug treatment against potential risks before prescribing this drug during pregnancy.
  • Clinical Management
The data on the use of novobiocin in pregnant women is limited. It has been noted that no malformations were observed in 21 patients exposed to novobiocin during the first trimester of pregnancy. However, use of novobiocin near term is not recommended because jaundice may develop due to inhibition of glucuronyl transferase.

Breastfeeding

  • Available evidence and/or expert consensus is inconclusive or is inadequate for determining infant risk when used during breastfeeding. Weigh the potential benefits of drug treatment against potential risks before prescribing this drug during breastfeeding.
  • Clinical Management
Until additional data are available, caution should be exercised with the use of novobiocin in women who breastfeed their infants.

Dosage and Administration

Normal Dosage

Oral route

  • The usual oral adult dose is 250 milligrams every 6 hours or 500 milligrams every 12 hours for treating serious infections due to susceptible S aureus or Proteus URINARY TRACT INFECTIONS when other less toxic antibiotics are contraindicated or ineffective.
  • Up to 500 milligrams every 6 hours or 1 gram every 12 hours of novobiocin may be administered orally for resistant or severe infections.
Dosage in Renal Failure
  • Dosage adjustment in renal failure is not indicated because less than 3% of a dose of novobiocin is eliminated in the urine.
Dosage in Hepatic Insufficiency
  • Dosage adjustment or discontinuation of novobiocin might be indicated if hepatic dysfunction develops.
Pediatric
Normal Dosage

Oral route

  • The usual daily, oral pediatric dose of novobiocin is 15 milligrams of novobiocin/kilogram body weight for moderate to acute infections, administered in divided doses every 6 to 12 hours.
  • Up to 30 to 45 milligrams of novobiocin/kilogram body weight may be administered orally in divided doses every 6 to 12 hours for resistant or severe infections.
  • Use of novobiocin should be avoided in newborn and young infants because of the possibility of inducing hyperbilirubinemia.

Therapeutic Uses

Infection due to Staphylococcus aureus

Excellent in-vitro activity against virtually all of the 103 strains of methicillin-resistant Staphylococcus aureus in one study.

Used in combination with rifampin in the treatment of methicillin-resistant Staphylococcus aureus.

  • Adult:
In the treatment of methicillin-resistant Staphylococcus aureus (MRSA), novobiocin is commonly used in combination with rifampin. This combination is not synergistic; however, it may prevent the emergence of resistant strains. In one study, novobiocin 500 milligrams 2 times daily, with rifampin 300 mg 2 times daily, both given orally for 5 days was effective in clearing MRSA in 79% of the courses administered to 12 patients. Some patients required repeated courses of treatment [4]. The usual dose of novobiocin is 20000 mg/day given in 4 divided doses orally. Novobiocin may also be administered intramuscularly or intravenously 500 mg every 8 hours.
Excellent in-vitro activity against virtually all of the 103 strains of METHICILLIN-RESISTANT STAPHYLOCOCCUS aureus was reported in one study. The reported MIC(90) and MBC(90) (minimum inhibitory and bacteriostatic concentrations necessary to affect 90% of bacteria) were 0.25 mg/liter with previously reported achievable serum concentrations with oral novobiocin of 100 to 200 times its MIC(90) against methicillin-resistant S aureus.
Urinary tract infectious disease
  • For treatment of susceptible urinary tract infections caused by Proteus species.
  • Novobiocin plus acidification of the urine was more effective than novobiocin therapy alone in eradicating gram-negative bacilli in the urine of patients with chronic bacteriuria.
  • Inadequate in treatment of gonococcal urethritis.

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

  1. ↑ 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. ↑ 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
  3. ↑ Hoeksema, H., Johnson, J. L., and Hinman, J. W. (1955). Structural studies on streptonivicin, a new antibiotic. J Am Chem Soc, 77, 6710-6711.
  4. ↑ 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. ↑ 5.0 5.1 Maxwell, A. (1993). The interaction between coumarin drugs and DNA gyrase. Mol Microbiol, 9, 681-686.
  6. ↑ Maxwell, A. (1999). DNA gyrase as a drug target. Biochem Soc Trans, 27, 48-53.
  7. ↑ Lewis, R. J., Tsai, F. T. F., and Wigley, D. B. (1996). Molecular mechanisms of drug inhibition of DNA gyrase. Bioessays, 18, 661-671.
  8. ↑ 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.
  9. ↑ 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. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ http://fda-drugs.legalview.com/legal-issue/albamycin/
  14. ↑ 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
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