RP 59500: a proposed mechanism for its bactericidal activity

RP 59500 is a combination of RP 57669 and RP 54476, which are semisynthetic water soluble derivatives of pristinamycin IA (PIA) and pristinamycin IIA (PIIA), respectively. Like their precursors, these molecules are bacteristatic in their own right. In association, they exert bactericidal activity against a variety of Gram-positive bacteria. Experiments involving the binding of these antibiotics to the target bacterial ribosome showed that both the binding sites and the mechanism of action of the components of RP 59500 are identical to those of the parent molecules. By affinity-labelling with a structural analogue of RP 57669, it was demonstrated that L24, a protein of the 70S ribosomal subunit, was specifically labelled. Experiments using radioactive N-ethylmaleimide to label proteins possessing a thiol residue, indicated that proteins L24, L10 and L11 are not only close to each other in the ribosomal structure, but are also adjacent (if not actually part of) the channel through which newly synthesized proteins are extruded. We propose that the mechanism of action of these compounds is to close or narrow the extrusion channel of these proteins, which could lead to their accumulation on the ribosome. We cannot exclude, of course, the possibility that this accumulation disturbs peptidyl-tRNA hydrolase (PHT) activity, thereby depleting free tRNAs within the cell and inhibiting protein synthesis.