Streptogramin: Definition, Mechanism and Example

What are streptogramin?

Streptogramin is an antibiotic produced from the soil genus Streptomyces. These antibiotics usually consist of two structurally different compounds: Streptogramin A (dalfopristin) and streptogramin group B (quinupristin). They inhibit bacterial protein synthesis by synergistically acting, thereby demonstrating bactericidal activity. Initially, streptogramin was mainly used in agriculture and animal husbandry until medicinal chemists discovered that they were effective natural antibiotics against VRSA (vancomycin-resistant Staphylococcus aureus). Therefore, many research institutions have been attracted to carry out semi-synthetic structural modifications on them. It was not until 1999 that the FDA approved the marketing of the first streptogramin antibiotic, synercid (a mixture of quinupristin/dalfopristin). It was mainly used in clinical practice for difficult to control methicillin-resistant Staphylococcus aureus (MRSA), multi-drug resistant bacteria, and vancomycin-resistant bacteria infections.

Streptogramin at BOC Sciences

Streptogramin A and streptogramin B

Streptogramin A is 23-membered unsaturated macrolide containing peptide bonds and lactone bonds, while streptogramins B is 19-membered cyclic hexapeptide lactone.

The biosynthesis of streptogramin A involves a hybrid polyketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS) system, an intricate enzymatic assembly line responsible for the molecule's complexity. The process begins with isobutyryl-CoA derived from valine, followed by sequential chain extensions using malonyl-CoA and the incorporation of amino acids such as glycine and D-proline. A notable step in this pathway includes the cyclization of serine-derived intermediates to form oxazole rings. Enzymes like VirA, VirF, and VirH coordinate these modifications, tailoring the molecule for its biological function.

In the case of streptogramin B, biosynthesis is carried out exclusively by NRPS enzymes. These large, multifunctional proteins operate through a modular design, with each module responsible for the activation, condensation, and modification of specific amino acids. Domains such as adenylation (A), peptidyl carrier protein (PCP), and condensation (C) ensure precise assembly, while additional domains like epimerization (E) or methyltransferase (MT) introduce stereochemical diversity. The final product is cyclized and released by a thioesterase (TE) domain, forming the biologically active cyclic depsipeptide.

Streptogramin mechanism of action

Streptogramin A and streptogramin B achieve bactericidal activity by synergistically inhibiting bacterial ribosomes. These two compounds bind to different positions of the 50S subunit of the bacterial ribosome, forming a stable drug-ribosome triad, thereby preventing the binding of aminoacyl tRNA and the translation process of the peptide-transferase center. Streptogramin A affects the early stages of protein synthesis, blocking the binding of aminoacyl tRNA complexes to the ribosome, causing obstacles to protein elongation. Streptogramin B affects late stages of protein synthesis, blocking peptide bond synthesis and promoting the early release of incomplete peptide chains.

Type A and type B streptogramins can be antibacterial drugs alone, but the combination of the two has a dual blocking effect on protein synthesis, and the antibacterial activity is enhanced 816 times that of single drugs. The reason is that the conformational change of the ribosome induced by the A component increases the binding affinity of the B component to the ribosome, thereby more effectively preventing the binding and translation process of aminoacyl tRNA. This synergistic mechanism makes streptogramin antibiotics a class of highly effective antibacterial drugs.

For example, in clinically used Synercid, dalfopristin first binds to the 50S ribosomal subunit and induces a conformational change, thereby promoting the binding of quinupristin. Dalfopristin prevents the extension of the peptide chain, while quinupristin triggers premature release of the peptide chain from the ribosome.

Streptogramin antibiotics also have the ability to overcome certain resistance mutations due to their ability to enhance binding of SB compounds by rotating nucleotide A2062 in the 23S rRNA. This mechanism allows streptogramin to effectively fight some drug-resistant strains, such as MRSA.

Streptogramins example

Pristinamycin is an unnatural combination of streptogramin A (pristinamycin IIA) and streptogramin B (pristinamycin IA). It's made by Streptomyces pristinaespiralis, and has long been a topical antibiotic for Gram-positive (mainly Staphylococcus aureus) infections. Pristinamycin's molecular complexity shows us the synergistic mechanism of action of the streptogramin class. It was effective, but it has been clinically unproven as it is insoluble in water, making it difficult to give intravenously.

Synercid is a semi-synthetic variant of natural streptogramins and is one example of pharmaceutical progress in this category. Synercid was approved by the FDA in 1999 – a 3:7 mix of quinupristin (a streptogramin B derivative) and dalfopristin (a streptogramin A derivative). It's a formulation made for intravenous administration to overcome the solubility problem with natural streptogramins.

Chemical structure of synercid. (Li, Q., 2020)

Streptomyces virginiae's streptogramin, virginiamycin, is another popular typus of streptogramins, used in agriculture as a growth and anti-infection feed supplement. This drug is made up of streptogramin A (virginiamycin M1) and streptogramin B (virginiamycin S1) that, when combined, inhibit bacterial protein production. It has worked well in agriculture, but fears of antibiotic resistance have led to tougher regulations in recent years.

Mikamycin and vernamycin are both streptogramins published in the literature, sometimes referred to as structural cousins of Pristinamycin or Virginiamycin. These molecules are useful to highlight molecular repeating patterns within the streptogramin family, but they're also useful as research probes of how bacteria inhibit and build resistance.

Streptosporin antibiotics uses

Treat skin or subcutaneous tissue infections caused by MSSA, MRSA, and methicillin-resistant coagulase-negative Staphylococcus (MRCNS). Studies have shown that MRSA and MRCNS are highly sensitive to quinupristin/dalfopristin, with drug resistance rates of 0.7% and 0.6%, respectively.

Treat vancomycin-resistant enterococcus faecium (VREF) infections. Enterococcus faecalis can carry the lsa gene and is resistant to dalfopristin, therefore, quinupristin/dalfopristin should not be used in people infected with Enterococcus faecalis. Quinupristin/dalfopristin has antibacterial activity against VREF. When Enterococcus faecium is resistant to vancomycin and daptomycin, quinopril/dafopril can be used as an alternative drug. It was reported in the literature that a patient with daptomy-resistant VREF-induced endocarditis recovered after 6 weeks of anti-infection with quinupristin/dalfopristin.

Reference

1. Li, Q., et al. Synthetic group A streptogramin antibiotics that overcome Vat resistance. Nature. 2020, 586(7827), 145-150.