title: Macrolones Are a Novel Class of Macrolide Antibiotics Active against Key Resistant Respiratory Pathogens In Vitro and In Vivo.
abstract: As we face an alarming increase in bacterial resistance to current antibacterial chemotherapeutics, expanding the available therapeutic arsenal in the fight against resistant bacterial pathogens causing respiratory tract infections is of high importance. The antibacterial potency of macrolones, a novel class of macrolide antibiotics, against key respiratory pathogens was evaluated in vitro and in vivo MIC values against Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and Haemophilus influenzae strains sensitive to macrolide antibiotics and with defined macrolide resistance mechanisms were determined. The propensity of macrolones to induce the expression of inducible erm genes was tested by the triple-disk method and incubation in the presence of subinhibitory concentrations of compounds. In vivo efficacy was assessed in a murine model of S. pneumoniae-induced pneumonia, and pharmacokinetic (PK) profiles in mice were determined. The in vitro antibacterial profiles of macrolones were superior to those of marketed macrolide antibiotics, including the ketolide telithromycin, and the compounds did not induce the expression of inducible erm genes. They acted as typical protein synthesis inhibitors in an Escherichia coli transcription/translation assay. Macrolones were characterized by low to moderate systemic clearance, a large volume of distribution, a long half-life, and low oral bioavailability. They were highly efficacious in a murine model of pneumonia after intraperitoneal application even against an S. pneumoniae strain with constitutive resistance to macrolide-lincosamide-streptogramin B antibiotics. Macrolones are the class of macrolide antibiotics with an outstanding antibacterial profile and reasonable PK parameters resulting in good in vivo efficacy.
authors.affiliation: GlaxoSmithKline Research Centre Zagreb, Zagreb, Croatia hana.paljetak@mef.hr.
authors.forename: Hana
authors.initials: H
authors.lastname: Čipčić Paljetak
authors.affiliation: GlaxoSmithKline Research Centre Zagreb, Zagreb, Croatia.
authors.forename: Donatella
authors.initials: D
authors.lastname: Verbanac
authors.affiliation: GlaxoSmithKline Research Centre Zagreb, Zagreb, Croatia.
authors.forename: Jasna
authors.initials: J
authors.lastname: Padovan
authors.affiliation: GlaxoSmithKline Research Centre Zagreb, Zagreb, Croatia.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Dominis-Kramarić
authors.affiliation: GlaxoSmithKline Research Centre Zagreb, Zagreb, Croatia.
authors.forename: Željko
authors.initials: Ž
authors.lastname: Kelnerić
authors.affiliation: GlaxoSmithKline Research Centre Zagreb, Zagreb, Croatia.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Perić
authors.affiliation: GlaxoSmithKline Research Centre Zagreb, Zagreb, Croatia.
authors.forename: Mihailo
authors.initials: M
authors.lastname: Banjanac
authors.affiliation: GlaxoSmithKline Research Centre Zagreb, Zagreb, Croatia.
authors.forename: Gabrijela
authors.initials: G
authors.lastname: Ergović
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Nerrisa
authors.initials: N
authors.lastname: Simon
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: John
authors.initials: J
authors.lastname: Broskey
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Holmes
authors.affiliation: GlaxoSmithKline Research Centre Zagreb, Zagreb, Croatia.
authors.forename: Vesna
authors.initials: V
authors.lastname: Eraković Haber
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000235:genetics; D004926:Escherichia coli / Q000737:chemistry; D006193:Haemophilus influenzae / Q000187:drug effects / Q000254:growth & development; D048628:Ketolides / Q000494:pharmacology; D055231:Lincosamides / Q000494:pharmacology; D018942:Macrolides / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000382:microbiology; D014176:Protein Biosynthesis / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D013297:Streptococcus pyogenes / Q000187:drug effects / Q000254:growth & development; D025381:Streptogramin B / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D048628:Ketolides; D055231:Lincosamides; D018942:Macrolides; D011500:Protein Synthesis Inhibitors; D025381:Streptogramin B; D008780:Methyltransferases; C431709:ErmA protein, Bacteria; C106791:telithromycin