RECENT DEVELOPMENTS IN STREPTOGRAMIN RESEARCH

The streptogramins are a class of antibiotics remarkable for their ant ibacterial activity and their unique mechanism of action. These antibi otics are produced naturally, but the therapeutic use of the natural c ompounds is limited because they do not dissolve in water. New semisyn thetic derivatives, in particular the injectable streptogramin quinupr istin/dalfopristin, offer promise for treating the rising number of in fections that are caused by multiply resistant bacteria. The streptogr amins consist of two structurally unrelated compounds,group A and grou p B. The group A compounds are polyunsaturated macrolactones; the grou p B compounds are cyclic hexadepsipeptides. Modifications of the group B components have been mainly performed on the 3-hydroxypicolinoyl, t he 4-dimethylaminophenylalanine and the 4-oxo pipecolinic residues. Se mi-synthesis on this third residue led lo the water-soluble derivative quinupristin. Water-soluble group A derivatives were obtained by Mich ael addition of aminothiols to the dehydroproline ring of pristinamyci n IIA, followed by oxidation of the intermediate sulfide into the sulf one derivatives (i.e., dalfopristin). Water-soluble derivatives (both group A and group B) can now be obtained at the industrial scale. Modi fied group B compounds are now also being produced by mutasynthesis, v ia disruption of the papA gene. Mutasynthesis has proved particularly useful for producing PIE, the group B component of the oral streptogra min RPR 106972. The streptogramins inhibit bacterial growth by disrupt ing the translation of mRNA into protein. Both the group A and group B compounds bind to the peptidyltransferase domain of the bacterial rib osome. The group A compounds interfere with the elongation of the poly peptide chain by preventing the binding of aa-tRNA to the ribosome and the formation of peptide bonds, while the B compounds stimulate the d issociation of the peptidyl-tRNA and may also interfere with the relea se of the completed! polypeptide by blocking its access to the channel through which it normally leaves the ribosome. The synergy between th e group A and group B compounds appears to result from an enhanced aff inity 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 mix tures of the group A and B compounds, the combination of which is a mo re potent antibacterial agent than either type of compound alone. Wher eas the type A or type B compound alone has, in vitro and in animal mo dels of infection, a moderate bacteriostatic activity, the combination of the two has strong bacteriostatic activity and often bactericidal activity. Minimal inhibitory concentrations of quinupristin/dalfoprist in range from 0.20 to 1 mg/l for Streptococcus pneumonae, from 0.25 to 2 mg/l for Staphylococcus aureus and from 0.50 to 4 for Enterococcus faecium, the principal tar et organisms of this drug. Quinupristin/dal fopristin also has activity against mycoplasmas, Neisseria gonorrhoeae , Haemophilus influenz, Legionella spp. and Moraxella catarrhalis. Bac teria develop resistance to the streptogramins hy ribosomal modificati on, by producing inactivating enzymes, or by causing an efflux of the antibiotic. Dimethylation of an adenine residue in rRNA, a reaction th at is catalyzed by a methylase encoded by the erm gene class, affects the binding of group B compounds (as well as the macrolides and lincos amides; hence, MLSB resistance), but group A and B compounds usually m aintain their synergy and their bactericidal effect against MLSB-resis tant strains. erm genes are widespread both geographically and through out numerous bacterial genera. Several types of enzymes (acetyltransfe rases, hydrolases) have been identified that inactivate the group A or the group B compounds. Genes involved in streptogramin efflux have so Ear been found only in staphylococci, particularly in coagulase-negat ive species. These resistance mechanisms do not, at present, threaten the efficacy of the streptogramins in the clinical setting. Neverthele ss, new analogues, as well as other antibiotics will be needed if we a re to keep apace of infectious microorganisms, given their capacity to constantly evolve original strategies of resistance.