Streptogramin A
Streptogramin A is a group of
Biosynthesis
Streptogramin A is a polyketide 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.[citation needed]
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
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.[4]
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.[3]
Mode of action
By themselves, streptogramins A and B are
Recently, it has been reported how inhibition of the mitochondrial ribosome by streptogramins A (alone or in combination with streptogramins B) can block glioblastoma stem cell growth, thus allowing for potential repurposing of these antibiotics as antineoplastic agents.[6][7]
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.[2]
Resistance to streptogramins
Multiple mechanisms of streptogramin resistance have developed despite Synercid's fairly recent development. The three major mechanisms of resistance include active efflux, covalent target modification and antibiotic inactivation enzymes.[2]
References
Further reading
- LeFevre, J.; Glass, T.; Kolpak, M.; Kingston, D. (1983). "Biosynthesis of Antibiotics of the Virginiamycin Family, 2. Assignment of the13C-NMR Spectra of Virginiamycin M1and Antibiotic A2315A". J. Nat. Prod. 46 (4): 475–480. .