title: Studies of the novel ketolide ABT-773: transport, binding to ribosomes, and inhibition of protein synthesis in Streptococcus pneumoniae.
abstract: Macrolide resistance in Streptococcus pneumoniae has been associated with two main mechanisms: target modification by Erm methyltransferases and efflux by macrolide pumps. The ketolide ABT-773, which has a 3-keto group and no L-cladinose sugar, represents a new class of drugs with in vitro activity against a variety of resistant bacteria. Several approaches were undertaken to understand how ABT-773 was able to defeat resistance mechanisms. We demonstrated tighter ribosome binding of ABT-773 than erythromycin. We also showed that ABT-773 (i) accumulated in macrolide-sensitive S. pneumoniae at a higher rate than erythromycin, (ii) was able to bind with methylated ribosomes, though at lower affinities than with wild-type ribosomes, and (iii) accumulated in S. pneumoniae strains with the efflux-resistant phenotype.
authors.affiliation: Infectious Disease Research, Abbott Laboratories, Abbott Park, Illinois 60064-6217, USA.
authors.forename: J O
authors.initials: JO
authors.lastname: Capobianco
authors.forename: Z
authors.initials: Z
authors.lastname: Cao
authors.forename: V D
authors.initials: VD
authors.lastname: Shortridge
authors.forename: Z
authors.initials: Z
authors.lastname: Ma
authors.forename: R K
authors.initials: RK
authors.lastname: Flamm
authors.forename: P
authors.initials: P
authors.lastname: Zhong
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000096:biosynthesis; D001692:Biological Transport; D004352:Drug Resistance, Microbial; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D048628:Ketolides; D012270:Ribosomes / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D048628:Ketolides; D004917:Erythromycin; C405499:cethromycin