Streptogramin A
Encyclopedia
Streptogramin A is group of antibiotics within the larger family of antibiotics known as streptogramin
s. They are synthesized by the bacteria Streptomyces virginiae. The streptogramin family of antibiotics consists of two distinct groups: group A antibiotics contain a 23-membered unsaturated ring with lactone
and peptide
bonds while group B
antibiotics are depsipeptide
s (lactone-cyclized peptides). While structurally different, these two groups of antibiotics act synergistically, providing greater antibiotic activity than the combined activity of the separate components. These antibiotics have until recently been commercially manufactured as feed additives in agriculture, although today there is increased interest in their ability to combat antibiotic-resistant bacteria, particularly vancomycin-resistant bacteria.
in nature, but contains some amino acid components as well. Its gene cluster codes for a hybrid PKS-NRPS protein that consists of eight PKS modules and two NRPS modules. Other enzymes are required for tailoring of streptogramin A, particularly for the unusual methylation
reaction. The figure below shows the origins of the synthetic components of streptogramin A.
The streptogramin A PKS-NRPS is composed of 6 proteins: VirA contains modules 1 though 6; VirF, VirG, and VirH contain modules 6 through 10; VirI is the AT domain that acts for every PKS module; and VirJ contains the TE domain. The starter unit for the biosynthesis of streptogramin A is isobutyryl-CoA
, which is given by the amino acid valine
after it has undergone transamination
and branched-chain keto acid dehydrogenation. Two rounds of chain extension with malonate
follow. An NRPS module introduces a glycine
residue into the growing polyketide chain, followed by two more rounds of chain extension with malonate. At this point, four enzymes use acetyl-CoA
to add a methyl group to position 12 on the macromolecule. The mechanism of the reaction is proposed below. VirC and HMG-CoA synthase bear striking structural similarities and while the mechanism for VirC is not known, it can be proposed to be similar to that of HMG-CoA synthase.
Such an elaborate mechanism of methylation is necessary since SAM is not able to insert a methyl group onto a carbonyl carbon. Another round of malonate extension occurs, followed by the malonate's reaction with an adjacent serine extender to form an oxazole
ring. This reaction is catalyzed by a cyclization domain on the Ser9 NRPS module. The diagram below shows the biogenesis of the oxazole ring from serine and malonate.
Finally, a D-proline
residue is added to the chain, followed by hydroxylation and dehydration to form dehydroproline, which is thought to occur through a reverse Michael-type reaction.
In 1999 the FDA had approved Synercid, a drug containing streptogramins A and B in a 7:3 ratio respectively. This intravenously-injected drug is used to treat patients with bacteremia caused by vancomycin-resistant Enterococcus faecium.
Streptogramin
Streptogramins are a class of antibiotics.Streptogramins are effective in the treatment of vancomycin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus , two of the most rapidly-growing strains of multidrug-resistant bacteria...
s. They are synthesized by the bacteria Streptomyces virginiae. The streptogramin family of antibiotics consists of two distinct groups: group A antibiotics contain a 23-membered unsaturated ring with lactone
Lactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...
and peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
bonds while group B
Streptogramin B
Streptogramin B is a subgroup of the streptogramin antibiotics family. These natural products are cyclic hexa- or hepta depsipeptides produced by various members of the genus of bacteria Streptomyces...
antibiotics are depsipeptide
Depsipeptide
A depsipeptide is a peptide in which one or more of the amide bonds are replaced by ester bonds.Depsipeptides have often been used in research to probe the importance of hydrogen bond networks in protein folding kinetics and thermodynamics. They are also found in nature as natural products...
s (lactone-cyclized peptides). While structurally different, these two groups of antibiotics act synergistically, providing greater antibiotic activity than the combined activity of the separate components. These antibiotics have until recently been commercially manufactured as feed additives in agriculture, although today there is increased interest in their ability to combat antibiotic-resistant bacteria, particularly vancomycin-resistant bacteria.
Biosynthesis
Streptogramin A is a polyketidePolyketide
Polyketides are secondary metabolites from bacteria, fungi, plants, and animals. Polyketides are usually biosynthesized through the decarboxylative condensation of malonyl-CoA derived extender units in a similar process to fatty acid synthesis...
in nature, but contains some amino acid components as well. Its gene cluster codes for a hybrid PKS-NRPS protein that consists of eight PKS modules and two NRPS modules. Other enzymes are required for tailoring of streptogramin A, particularly for the unusual methylation
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
reaction. The figure below shows the origins of the synthetic components of streptogramin A.
The streptogramin A PKS-NRPS is composed of 6 proteins: VirA contains modules 1 though 6; VirF, VirG, and VirH contain modules 6 through 10; VirI is the AT domain that acts for every PKS module; and VirJ contains the TE domain. The starter unit for the biosynthesis of streptogramin A is isobutyryl-CoA
Isobutyryl-CoA
Isobutyryl-coenzyme A is an intermediate in the metabolism of valine.-See also:* Isobutyryl-CoA mutase* Isobutyryl-coenzyme A dehydrogenase deficiency...
, which is given by the amino acid valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
after it has undergone transamination
Transamination
There are two chemical reactions known as transamination . The first is the reaction between an amino acid and an alpha-keto acid...
and branched-chain keto acid dehydrogenation. Two rounds of chain extension with malonate
Malonate
The malonate or propanedioate ion is CH222− . Malonate compounds include salts and esters of malonic acid, such as*diethyl malonate, 2,*dimethyl malonate, 2,...
follow. An NRPS module introduces a glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
residue into the growing polyketide chain, followed by two more rounds of chain extension with malonate. At this point, four enzymes use acetyl-CoA
Acetyl-CoA
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
to add a methyl group to position 12 on the macromolecule. The mechanism of the reaction is proposed below. VirC and HMG-CoA synthase bear striking structural similarities and while the mechanism for VirC is not known, it can be proposed to be similar to that of HMG-CoA synthase.
Such an elaborate mechanism of methylation is necessary since SAM is not able to insert a methyl group onto a carbonyl carbon. Another round of malonate extension occurs, followed by the malonate's reaction with an adjacent serine extender to form an oxazole
Oxazole
Oxazole is the parent compound for a vast class of heterocyclic aromatic organic compounds. These are azoles with an oxygen and a nitrogen separated by one carbon. Oxazoles are aromatic compounds but less so than the thiazoles...
ring. This reaction is catalyzed by a cyclization domain on the Ser9 NRPS module. The diagram below shows the biogenesis of the oxazole ring from serine and malonate.
Finally, a D-proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
residue is added to the chain, followed by hydroxylation and dehydration to form dehydroproline, which is thought to occur through a reverse Michael-type reaction.
Mode of action
By themselves, streptogramins A and B are bacteriostatic. However, when used in conjunction with one another, the streptogramins can inhibit bacterial growth and are bactericidal. Streptogramin A first binds to the peptidyl transferase domain of the 50s ribosomal subunit, preventing the early events of elongation. The binding of streptogramin A causes a conformational change that increases the ribosomal binding activity of streptogramin B 100-fold. Upon binding the ribosome (which streptogramin B can accomplish at any stage of protein synthesis), streptogramin B prevents protein chain extension and can initiate the release of incomplete peptides. When both streptogramins are bound to the ribosome, they form an extremely stable ternary complex.In 1999 the FDA had approved Synercid, a drug containing streptogramins A and B in a 7:3 ratio respectively. This intravenously-injected drug is used to treat patients with bacteremia caused by vancomycin-resistant Enterococcus faecium.