Single- and multistep resistance selection studies on the activity of retapamulin compared to other agents against Staphylococcus aureus and Streptococcus pyogenes

Abstract

Retapamulin had the lowest rate of spontaneous mutations by single-step passaging and the lowest parent and selected mutant MICs by multistep passaging among all drugs tested for all Staphylococcus aureus strains and three Streptococcus pyogenes strains which yielded resistant clones. Retapamulin has a low potential for resistance selection in S. pyogenes, with a slow and gradual propensity for resistance development in S. aureus.

FIG. 1.

Chemical structure of retapamulin.

FIG. 2.

Mutations found in S. aureus and S. pyogenes multi- and single-passage mutants with reduced susceptibilities to retapamulin. The figures shows an alignment of various ribosomal protein L3 sequences in the regions flanking the mutations. The positions of the characterized mutations in S. aureus and S. pyogenes mutants are highlighted in a shade of gray; position 149 in E. coli and analogous positions in other sequences crucial for developing resistance are indicated with an asterisk; and positions of amino acid identity are highlighted in dark gray. Sequences: 1, parental S. aureus strain starting from amino acid position 142; 2, selected S. aureus mutant starting from position 142; 3, parental S. pyogenes strain starting from position 137; 4, selected S. pyogenes mutant starting from position 137; 5, E. coli starting from position 139; 6, Brachyspira hyodysenteriae and Brachyspira pilosicoli starting from position 139; 7, Deinococcus radiodurans starting from position 134; 8, Haloarcula marismortui starting from position 232; and 9, Saccharomyces cerevisiae starting from position 245.