RESUMO
Macrolide resistance mechanisms can be target-based with a change in a 23S ribosomal RNA (rRNA) residue or a mutation in ribosomal protein L4 or L22 affecting the ribosome's interaction with the antibiotic. Alternatively, mono- or dimethylation of A2058 in domain V of the 23S rRNA by an acquired rRNA methyltransferase, the product of an erm (erythromycin ribosome methylation) gene, can interfere with antibiotic binding. Acquired genes encoding efflux pumps, most predominantly mef(A) + msr(D) in pneumococci/streptococci and msr(A/B) in staphylococci, also mediate resistance. Drug-inactivating mechanisms include phosphorylation of the 2'-hydroxyl of the amino sugar found at position C5 by phosphotransferases and hydrolysis of the macrocyclic lactone by esterases. These acquired genes are regulated by either translation or transcription attenuation, largely because cells are less fit when these genes, especially the rRNA methyltransferases, are highly induced or constitutively expressed. The induction of gene expression is cleverly tied to the mechanism of action of macrolides, relying on antibiotic-bound ribosomes stalled at specific sequences of nascent polypeptides to promote transcription or translation of downstream sequences.
Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana/genética , Macrolídeos/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Metilação , Metiltransferases/genética , Testes de Sensibilidade Microbiana , RNA Bacteriano/genética , RNA Ribossômico 23S/genética , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Streptococcus pneumoniae/genéticaRESUMO
We describe novel rifamycin derivatives (new chemical entities [NCEs]) that retain significant activity against a comprehensive collection of Staphylococcus aureus strains that are resistant to rifamycins. This collection of resistant strains contains 21 of the 26 known single-amino-acid alterations in RpoB, the target of rifamycins. Some NCEs also demonstrated a lower frequency of resistance development than rifampin and rifalazil in S. aureus as measured in a resistance emergence test. When assayed for activity against the strongest rifamycin-resistant mutants, several NCEs had MICs of 2 microg/ml, in contrast to MICs of rifampin and rifalazil, which were 512 microg/ml for the same strains. The properties of these NCEs therefore demonstrate a significant improvement over those of earlier rifamycins, which have been limited primarily to combination therapy due to resistance development, and suggest a potential use of these NCEs for monotherapy in several clinical indications.
