Overcoming bacterial resistance by dual target inhibition: the case of streptogramins.

Streptogramins A and B are chemically unrelated antimicrobials which act synergistically. This synergy is responsible for enhanced activity of the combination compared to each of the components and allows to overcome certain mechanisms of resistance to streptogramins B.. Although not completely elucidated, the mechanism of synergy is unique and based on a stable ribosome conformational change provoked by the binding of streptogramins A which unmasks a high affinity binding site for streptogramins B. A variety of resistance mechanisms to the A or B components by drug inactivation, target site modification, and active efflux have been reported. Acquired resistance to streptogramins A partially alters the synergy between the streptogramins A and B confirming the role of this component in the synergy. Full resistance in clinical isolates is due to combinations of genes for resistance to both components often associated on a single plasmid. Recently, a mutation in the L22 ribosomal protein of Staphylococcus aureus was found to confer resistance to streptogramins B and to abolish the synergy between A and B, probably by perturbing the association of this protein with 23S rRNA.