Aminocoumarin Explained

Aminocoumarin is a class of antibiotics that act by an inhibition of the DNA gyrase enzyme involved in the cell division in bacteria. They are derived from Streptomyces species,[1] whose best-known representative – Streptomyces coelicolor – was completely sequenced in 2002.[2] The aminocoumarin antibiotics include:[3]

Structure

The core of aminocoumarin antibiotics is made up of a 3-amino-4,7-dihydroxycumarin ring, which is linked, e.g., with a sugar in 7-Position and a benzoic acid derivative in 3-Position.

Clorobiocin is a natural antibiotic isolated from several Streptomyces strains and differs from novobiocin in that the methyl group at the 8 position in the coumarin ring of novobiocin is replaced by a chlorine atom, and the carbamoyl at the 3' position of the noviose sugar is substituted by a 5-methyl-2-pyrrolylcarbonyl group.

Mechanism of action

The aminocoumarin antibiotics are known inhibitors of DNA gyrase. Antibiotics of the aminocoumarin family exert their therapeutic activity by binding tightly to the B subunit of bacterial DNA gyrase, thereby inhibiting this essential enzyme.[4] They compete with ATPfor binding to the B subunit of this enzyme and inhibit the ATP-dependent DNA supercoiling catalysed by gyrase.[5] X-ray crystallography studies have confirmed binding at the ATP-binding site located on the gyrB subunit of DNA gyrase.[6] Their affinity for gyrase is considerably higher than that of modern fluoroquinolones, which also target DNA gyrase but at the gyrA subunit.[7]

Resistance

Resistance to this class of antibiotics usually results from genetic mutation in the gyrB subunit.[8] Other mechanisms include de novo synthesis of a coumarin-resistant gyrase B subunit by the novobiocin producer S. sphaeroides .[7]

Clinical use

The clinical use of this antibiotic class has been restricted due to the low water solubility, low activity against gram-negative bacteria,[5] and toxicity in vivo of this class of antibiotics.[9]

Notes and References

  1. Book: L.. Complex Enzymes in Microbial Natural Product Biosynthesis, Part B: Polyketides, Aminocoumarins and Carbohydrates. Heide. Chapter 18 Aminocoumarins. 459. 437–455. 2009. 10.1016/S0076-6879(09)04618-7. 19362650. Methods in Enzymology. 9780123745910.
  2. Bentley . SD . etal . 2002 . Complete genome sequence of the model actinomycete "Streptomyces coelicolor" A3(2) . Nature . 417 . 6885. 141–147 . 10.1038/417141a . 12000953. 2002Natur.417..141B . 4430218 . free .
  3. Book: Antibiotics: Targets, Mechanisms and Resistance. A Chemist’s Survey of Different Antibiotic Classes. Sonia Ilaria Maffioli. Claudio O. Gualerzi . Letizia Brandi . Attilio Fabbretti . Cynthia L. Pon.. 2014. Wiley-VCH. 9783527659685.
  4. Galm, Ute, Heller, Stefanie, Shapiro, Stuart, Page, Malcolm, Li, Shu-Ming, Heide, LutzAntimicrobial and DNA Gyrase-Inhibitory Activities of Novel Clorobiocin Derivatives Produced by Mutasynthesis Antimicrob. Agents Chemother. 2004 48: 1307–1312
  5. Maxwell . A. . Lawson . D. M. . 2003 . The ATP-binding site of type II topoisomerases as a target for antibacterial drugs . Curr Top Med Chem . 3 . 3. 283–303 . 10.2174/1568026033452500 . 12570764.
  6. Tsai . F.T.F. . Singh . O.M. . Wonacott . A.J. . Weston . S. . Tucker . A. . Pauptit . R.A. . Breeze . A.L. . Poyser . J.P. . O'Brien . R. . etal . 1997 . 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 . 1. 41–52 . 10.1002/(sici)1097-0134(199705)28:1<41::aid-prot4>3.3.co;2-b. 9144789 .
  7. Schmutz . E . Mühlenweg . A . Li . SM . Heide . L . 2003 . Resistance genes of aminocoumarin producers: two type II topoisomerase genes confer resistance against coumermycin A1 and clorobiocin . Antimicrob Agents Chemother . 47 . 3. 869–77 . 10.1128/aac.47.3.869-877.2003. 12604514 . 149333 .
  8. Fujimoto-Nakamura . M. . Ito . H. . Oyamada . Y. . Nishino . T. . Yamagishi . J.-I. . 2005 . Accumulation of Mutations in both gyrB and parE Genes Is Associated with High-Level Resistance to Novobiocin in Staphylococcus aureus . Antimicrob. Agents Chemother. . 49 . 9. 3810–3815 . 10.1128/aac.49.9.3810-3815.2005 . 16127057 . 1195401.
  9. A. Maxwell, The interaction between coumarin drugs and DNA gyrase. Mol. Microbiol. 9 (1993), pp. 681–686.

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