Recent Developments in Streptogramin Research
Authors: Desnuttes J.P. , Barriere J.C. , Berthaud N. , Beyer D. , Dutka-Malen S. , Paris J.M. 
Published: October 2022

Abstract:
The streptogramins are a class of antibiotics remarkable for their antibacterial activity and their unique mechanism of action. These antibiotics are produced naturally, but the therapeutic use of the natural compounds is limited because they do not dissolve in water. New semisynthetic derivatives, in particular the injectable streptogramin quinupristin/dalfopristin, offer promise for treating the rising number ol infections that are caused by multiply resistant bacteria.
The streptogramins consist of two structurally unrelated compounds, group A and group B. The group A compounds are polyunsaturated macrolactones; the group B compounds are cyclic hexadepsipeptides. Modifications of the group B components have been mainly performed on the 3-hydroxypicolinoyl, the 4- dimethylaminophenylalanine and the 4-oxo pipecolinic residues. Semi-synthesis on this third residue led to the water-soluble derivative quinupristin. Water-soluble group A derivatives were obtained by Michael addition of aminothiols to the dehydroproline ring of pristinamycin IIA, followed by oxidation of the intermediate sulfide into the sulfone d_erivatives (i.e., dalfopristin). Water-soluble derivatives (both group A and group B) can now be obtained at the industrial scale. Modified group B compounds are now also being produced by mutasynthesis, via disruption of the papA gene. Mutasynthesis has proved particularly useful for producing PIB, the group B component of the oral streptogramin RPR 106972.
The streptogramins inhibit bacterial growth by disrupting the translation of mRNA into protein. Both the group A and group B compounds bind to the peptidyltransferase domain of the bacterial ribosome. The group A compounds interfere with the elongation of the polypeptide chain by preventing the binding of aa-tRNA to the ribosome and the formation of peptide bonds, while the B compounds stimulate the dissociation of the peptidyl­ tRNA and may also interfere with the release of the completed polypeptide by blocking its access to the channel through which it normally leaves the ribosome. The synergy between the group A and group B compounds appears to result from an enhanced affinity of the group B compounds for the ribosome. Apparently, the group A compound induces a conformational change such that B compound binds with greater affinity.
The natural streptogramins are produced as mixtures of the group A and B compounds, the combination of which is a more potent antibacterial agent than either type of compound alone. Whereas the type A or type B compound alone has, in vitro and in animal models of infection, a moderate bacteriostatic activity, the combination of the two has strong bacteriostatic activity and often bactericidal activity. Minimal inhibitory concentrations of quinupristin/dalfopristin range from 0.20 to I mg/I for Streptococcus pneumonae, from 0.25 to 2 mg/I for Staphylococcus aureus and from 0.50 to 4 for Enterococcus faecium, the principal target organisms of this drug. Quinupristin/dalfopristin also has activity against mycoplasmas, Neisseriu gonorrhoeae, Haemophilus influenz, Legionella spp. and Moraxella catarrhalis.
Bacteria develop resistance to the streptogramins by ribosomal modification, by producing inactivating enzymes, or by causing an efflux of the antibiotic. Dimethylation of an adenine residue in rRNA, a reaction that is catalyzed by a methylase encoded by the erm gene class, affects the binding of group B compounds (as well as the macrolides and lincosamides; hence, MLS8 resistance), but group A and B compounds usually maintain their synergy and their bactericidal effect against MLS8-resistant strains. erm genes are widespread both geographically and throughout numerous bacterial genera. Several types of enzymes (acetyltransferases, hydrolases) have been identified that inactivate the group A or the group B compounds. Genes involved in streptogramin efflux have so far been found only in staphylococci, particularly in coagulase-negative species.
These resistance mechanisms do not, at present, threaten the efficacy of the streptogramins in the clinical setting. Nevertheless, new analogues. as well as other antibiotics will be needed if we are to keep apace of infectious microorganisms, given their capacity to constantly evolve original strategies of resistance.