Aminocoumarin is a class of

antibiotics An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention o ...

that act by an inhibition of the

DNA gyrase DNA gyrase, or simply gyrase, is an enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrat ...

enzyme involved in the cell division in

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...

. They are derived from ''

Streptomyces ''Streptomyces'' is the largest genus of Actinomycetota and the type genus of the family Streptomycetaceae. Over 500 species of ''Streptomyces'' bacteria have been described. As with the other Actinomycetota, streptomycetes are gram-positive, ...

'' species, whose best-known representative – ''

Streptomyces coelicolor ''Streptomyces albidoflavus'' is a bacterium species from the genus of ''Streptomyces'' which has been isolated from soil from Poland. ''Streptomyces albidoflavus'' produces dibutyl phthalate and streptothricins. Small noncoding RNA Bacteri ...

'' – was completely

sequenced In genetics and biochemistry, sequencing means to determine the primary structure (sometimes incorrectly called the primary sequence) of an unbranched biopolymer. Sequencing results in a symbolic linear depiction known as a sequence which suc ...

in 2002. The aminocoumarin antibiotics include: *

Novobiocin Novobiocin, also known as albamycin or cathomycin, is an aminocoumarin antibiotic that is produced by the actinomycete '' Streptomyces niveus'', which has recently been identified as a subjective synonym for ''S. spheroides'' a member of the clas ...

, Albamycin (

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And

Upjohn The Upjohn Company was a pharmaceutical manufacturing firm founded in 1886 in Hastings, Michigan, by Dr. William E. Upjohn who was an 1875 graduate of the University of Michigan medical school. The company was originally formed to make ''friabl ...

) *

Coumermycin Coumermycin A1 is an aminocoumarin. Its main target is the ATPase site of the DNA Gyrase GyrB subunit . See also Chemically induced dimerization Chemically Induced Dimerization (CID) is a biological mechanism in which two proteins bind only in ...

Clorobiocin Clorobiocin is an aminocoumarin antibacterial that inhibits the enzyme DNA gyrase DNA gyrase, or simply gyrase, is an enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upo ...

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 ''

'' strains and differs from

novobiocin Novobiocin, also known as albamycin or cathomycin, is an aminocoumarin antibiotic that is produced by the actinomycete '' Streptomyces niveus'', which has recently been identified as a subjective synonym for ''S. spheroides'' a member of the clas ...

in that the methyl group at the 8 position in the coumarin ring of

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

Antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...

s of the aminocoumarin family exert their therapeutic activity by binding tightly to the B subunit of bacterial

, thereby inhibiting this essential enzyme. They compete with ATP for binding to the B subunit of this enzyme and inhibit the ATP-dependent DNA supercoiling catalysed by gyrase. X-ray crystallography studies have confirmed binding at the ATP-binding site located on the gyrB subunit of

. Their

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for gyrase is considerably higher than that of modern

fluoroquinolones A quinolone antibiotic is a member of a large group of broad-spectrum antibiotic, broad-spectrum bacteriocidals that share a bicyclic molecule, bicyclic core structure related to the substance 4-Quinolone, 4-quinolone. They are used in human and ...

, which also target DNA gyrase but at the gyrA subunit.

Resistance

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

Clinical use

The clinical use of this antibiotic class has been restricted due to the low water solubility, low activity against gram-negative bacteria, and toxicity ''in vivo'' of this class of antibiotics.A. Maxwell, The interaction between coumarin drugs and DNA gyrase. ''Mol. Microbiol''. 9 (1993), pp. 681–686.

References

{{Nucleic acid inhibitors Antibiotics Coumarin drugs