RESUMEN
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.
Asunto(s)
Antibacterianos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Macrólidos/farmacología , Neumonía Neumocócica/tratamiento farmacológico , Inhibidores de la Síntesis de la Proteína/farmacología , Streptococcus pneumoniae/efectos de los fármacos , Animales , Antibacterianos/farmacocinética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Modelos Animales de Enfermedad , Farmacorresistencia Bacteriana/genética , Escherichia coli/química , Haemophilus influenzae/efectos de los fármacos , Haemophilus influenzae/crecimiento & desarrollo , Cetólidos/farmacología , Lincosamidas/farmacología , Macrólidos/farmacocinética , Masculino , Metiltransferasas/genética , Metiltransferasas/metabolismo , Ratones , Ratones Endogámicos C57BL , Neumonía Neumocócica/microbiología , Biosíntesis de Proteínas/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/farmacocinética , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/crecimiento & desarrollo , Streptococcus pyogenes/efectos de los fármacos , Streptococcus pyogenes/crecimiento & desarrollo , Estreptogramina B/farmacología , Relación Estructura-ActividadRESUMEN
Two series of clarithromycin and azithromycin derivatives with terminal 6-alkylquinolone-3-carboxylic unit with central ether bond in the linker were prepared and tested for antimicrobial activity. Quinolone-linker intermediates were prepared by Sonogashira-type C(6)-alkynylation of 6-iodo-quinolone precursors. In the last step, 4'' site-selective acylation of 2'-protected macrolides was completed with the EDC reagent, which selectively activated a terminal, aliphatic carboxylic group in dicarboxylic intermediates. Antimicrobial activity of the new series of macrolones is discussed. The most potent compound, 4''-O-{6-[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydroquinolin-6-yl)-propoxy]-hexanoyl}-azithromycin (10), is highly active against bacterial respiratory pathogens resistant to macrolide antibiotics and represents a promising lead for further investigation.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Azitromicina/análogos & derivados , Claritromicina/análogos & derivados , Macrólidos/síntesis química , Quinolonas/síntesis química , Antibacterianos/química , Azitromicina/química , Azitromicina/farmacología , Claritromicina/química , Claritromicina/farmacología , Humanos , Macrólidos/química , Macrólidos/farmacología , Pruebas de Sensibilidad Microbiana , Quinolonas/química , Quinolonas/farmacología , Relación Estructura-ActividadRESUMEN
The in vitro activity of retapamulin was determined and compared to that of topical and community antibiotics. The MIC(90)s of retapamulin against Staphylococcus aureus and Streptococcus pyogenes were 0.12 microg/ml and 0.016 microg/ml, respectively. Retapamulin has a low propensity to select resistance and produces an in vitro postantibiotic effect.
Asunto(s)
Antiinfecciosos Locales/farmacología , Bacterias/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Diterpenos/farmacología , Farmacorresistencia Bacteriana , Haemophilus influenzae/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Moraxella catarrhalis/efectos de los fármacos , Mupirocina/farmacología , Compuestos Policíclicos , Enfermedades Cutáneas Bacterianas/microbiología , Staphylococcus/efectos de los fármacos , Streptococcus/efectos de los fármacos , PleuromutilinasRESUMEN
Pantothenate kinase (CoaA) catalyzes the first step of the coenzyme A biosynthetic pathway. Here we report the identification of the Staphylococcus aureus coaA gene and characterization of the enzyme. We have also identified a series of low-molecular-weight compounds which are effective inhibitors of S. aureus CoaA.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Fosfotransferasas (Aceptor de Grupo Alcohol)/antagonistas & inhibidores , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/enzimología , Adenosina Trifosfato/metabolismo , Secuencia de Aminoácidos , Secuencia de Bases , Clonación Molecular , Coenzima A/biosíntesis , ADN Bacteriano/química , ADN Bacteriano/genética , Humanos , Concentración 50 Inhibidora , Cinética , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Ácido Pantoténico/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Filogenia , Alineación de Secuencia , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genética , Células Tumorales CultivadasRESUMEN
Homologues of Escherichia coli bacA, encoding extremely hydrophobic proteins, were identified in the genomes of Staphylococcus aureus and Streptococcus pneumoniae. Allelic replacement mutagenesis demonstrated that the gene is not essential for in vitro growth in either organism, and the mutants showed no significant changes in growth rate or morphology. The Staph. aureus bacA mutant showed slightly reduced virulence in a mouse model of infection and an eightfold increase in bacitracin susceptibility. However, a Strep. pneumoniae bacA mutant was highly attenuated in a mouse model of infection, and demonstrated an increase in susceptibility to bacitracin of up to 160000-fold. These observations are consistent with the previously proposed role of BacA protein as undecaprenol kinase.