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.[citation needed]
Clorobiocin is a natural antibiotic isolated from severalStreptomyces strains and differs fromnovobiocin in that the methyl group at the 8 position in the coumarin ring ofnovobiocin 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.[4]
The aminocoumarin antibiotics are known inhibitors ofDNA 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.[5] They compete with ATPfor binding to the B subunit of this enzyme and inhibit the ATP-dependent DNA supercoiling catalysed by gyrase.[6] X-ray crystallography studies have confirmed binding at the ATP-binding site located on the gyrB subunit of DNA gyrase.[4] Theiraffinity for gyrase is considerably higher than that of modernfluoroquinolones, which also target DNA gyrase but at the gyrA subunit.[7]
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 producerS. sphaeroides.[7]
The clinical use of this antibiotic class has been restricted due to the low water solubility, low activity against gram-negative bacteria,[6] and toxicityin vivo of this class of antibiotics.[9]
^Heide, L. (2009). "Chapter 18 Aminocoumarins".Complex Enzymes in Microbial Natural Product Biosynthesis, Part B: Polyketides, Aminocoumarins and Carbohydrates. Methods in Enzymology. Vol. 459. pp. 437–455.doi:10.1016/S0076-6879(09)04618-7.ISBN9780123745910.PMID19362650.
^Sonia Ilaria Maffioli (2014). "A Chemist's Survey of Different Antibiotic Classes". In Claudio O. Gualerzi; Letizia Brandi; Attilio Fabbretti; Cynthia L. Pon. (eds.).Antibiotics: Targets, Mechanisms and Resistance. Wiley-VCH.ISBN9783527659685.
^abTsai, 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.; et al. (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.doi:10.1002/(sici)1097-0134(199705)28:1<41::aid-prot4>3.3.co;2-b.PMID9144789.
^abMaxwell, 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.doi:10.2174/1568026033452500.PMID12570764.
