RESUMEN
Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S. aureus MIC90=0.125µg/mL) and in vivo (systemic and tissue infections). Enhanced inhibition of Topoisomerase IV correlated with improved activity in S. aureus strains with mutations conferring resistance to NBTIs. Compound 14 also displayed an improved hERG IC50 of 85.9µM and a favorable profile in the anesthetized guinea pig model.
Asunto(s)
Antibacterianos/farmacología , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/antagonistas & inhibidores , Quinolinas/farmacología , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Topoisomerasa de ADN IV/metabolismo , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/metabolismo , Cobayas , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Quinolinas/síntesis química , Quinolinas/química , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Streptococcus pyogenes/efectos de los fármacos , Streptococcus pyogenes/enzimología , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa/síntesis química , Inhibidores de Topoisomerasa/químicaRESUMEN
In over a decade (2002 to 2012) of Staphylococcus aureus surveillance testing on 62,195 isolates, dalbavancin was demonstrated to be active against isolates that were either susceptible or nonsusceptible to daptomycin, linezolid, or tigecycline. Nearly all (99.8%) multidrug-resistant methicillin-resistant S. aureus isolates were inhibited by dalbavancin at ≤0.12 µg/ml (MIC50/90, 0.06/0.06 µg/ml), the current U.S. Food and Drug Administration (U.S. FDA) breakpoint. Overall, only 0.35% of the monitored S. aureus isolates had a dalbavancin MIC of either 0.25 or 0.5 µg/ml (i.e., were nonsusceptible).
Asunto(s)
Antibacterianos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Infecciones Estafilocócicas/tratamiento farmacológico , Teicoplanina/análogos & derivados , Daptomicina/farmacología , Farmacorresistencia Bacteriana Múltiple , Monitoreo Epidemiológico , Humanos , Linezolid/farmacología , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Minociclina/análogos & derivados , Minociclina/farmacología , Teicoplanina/farmacología , Tigeciclina , Estados UnidosRESUMEN
A novel series of 3-O-carbamoyl erythromycin A derived analogs, labeled carbamolides, with activity versus resistant bacterial isolates of staphylococci (including macrolide and oxazolidinone resistant strains) and streptococci are reported. An (R)-2-aryl substituent on a pyrrolidine carbamate appeared to be critical for achieving potency against resistant strains. Crystal structures showed a distinct aromatic interaction between the (R)-2-aryl (3-pyridyl for 4d) substituent on the pyrrolidine and G2484 (G2505, Escherichia coli) of the Deinococcus radiodurans 50S ribosome (3.2Å resolution).
Asunto(s)
Antibacterianos/química , Eritromicina/análogos & derivados , Compuestos de Metilurea/química , Staphylococcus/aislamiento & purificación , Streptococcus/aislamiento & purificación , Antibacterianos/síntesis química , Sitios de Unión , Cristalografía por Rayos X , Deinococcus/metabolismo , Farmacorresistencia Bacteriana , Eritromicina/síntesis química , Escherichia coli/metabolismo , Pruebas de Sensibilidad Microbiana , Estructura Terciaria de Proteína , Pirrolidinas/química , Subunidades Ribosómicas Grandes Bacterianas/química , Subunidades Ribosómicas Grandes Bacterianas/metabolismo , Staphylococcus/efectos de los fármacos , Streptococcus/efectos de los fármacosRESUMEN
A structurally novel set of inhibitors of bacterial type II topoisomerases with potent in vitro and in vivo antibacterial activity was developed. Dual-targeting ability, hERG inhibition, and pharmacokinetic properties were also assessed.
Asunto(s)
Antibacterianos/farmacología , Topoisomerasa de ADN IV/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Quinolinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Inhibidores de Topoisomerasa II , Animales , Antibacterianos/administración & dosificación , Antibacterianos/química , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/metabolismo , ADN-Topoisomerasas de Tipo II/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Quinolinas/administración & dosificación , Quinolinas/química , Ratas , Staphylococcus aureus/enzimología , Streptococcus pneumoniae/enzimología , Relación Estructura-ActividadRESUMEN
Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MDR Gram-negative pathogens are described.
Asunto(s)
Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Monobactamas/farmacología , Animales , Sitios de Unión/efectos de los fármacos , Proteínas Sanguíneas/química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Infecciones por Bacterias Gramnegativas/microbiología , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Monobactamas/síntesis química , Monobactamas/química , Ratas , Relación Estructura-ActividadRESUMEN
In vitro activities of delafloxacin and ciprofloxacin were evaluated against Burkholderia pseudomallei mutants expressing or lacking defined resistance-nodulation-cell division (RND) efflux pumps using CLSI methodology at pHs of 5.8 and 7.2. Delafloxacin MIC values were as much as 8-fold lower at pH 5.8 than those at pH 7.2, while ciprofloxacin MICs increased as much as 8-fold. The data from this study suggest that compared to ciprofloxacin, delafloxacin may have improved efflux avoidance, notably at acidic pH. In contrast to ciprofloxacin, delafloxacin may thus retain its therapeutic potential, even in BpeEF-OprC efflux-pump-expressing B. pseudomallei strains that compromise the use of fluoroquinolones, such as ciprofloxacin. IMPORTANCE Resistance-nodulation-cell division (RND) efflux pumps play a major role in intrinsic and acquired antibiotic resistance in Burkholderia pseudomallei, and these pumps are its only known multidrug resistance determinants. Fluoroquinolones have performed poorly in clinical settings and are currently not recommended for treatment of B. pseudomallei infections. While the reasons for the poor clinical performance of this pathogen remain unclear, efflux may be partially responsible since fluoroquinolones like ciprofloxacin are prone to efflux by RND pumps, notably BpeEF-OprC. In vitro efficacy testing using a panel of efflux-proficient and efflux-deficient strains allows identification of fluoroquinolones that compared to ciprofloxacin are less prone to efflux.
Asunto(s)
Burkholderia pseudomallei , Burkholderia pseudomallei/genética , Farmacorresistencia Bacteriana Múltiple , Antibacterianos/farmacología , Fluoroquinolonas/farmacología , Pruebas de Sensibilidad Microbiana , Ciprofloxacina/farmacologíaRESUMEN
We report a multicity outbreak of cfr-containing linezolid-resistant Staphylococcus epidermidis in Ohio. Thirty-nine isolates were obtained from 2 hospitals. Two clones with different mechanisms of linezolid resistance were circulating in hospital A. One of these contained the cfr gene, and the other a ribosomal mutation. The clone containing cfr was identical in both hospitals.
Asunto(s)
Acetamidas/farmacología , Antibacterianos/farmacología , Brotes de Enfermedades , Farmacorresistencia Bacteriana , Oxazolidinonas/farmacología , Infecciones Estafilocócicas/epidemiología , Infecciones Estafilocócicas/microbiología , Staphylococcus epidermidis/efectos de los fármacos , Proteínas Bacterianas/genética , Técnicas de Tipificación Bacteriana , Dermatoglifia del ADN , ADN Bacteriano/genética , Electroforesis en Gel de Campo Pulsado , Genotipo , Hospitales , Humanos , Linezolid , Ohio/epidemiología , Staphylococcus epidermidis/aislamiento & purificaciónRESUMEN
OBJECTIVES: The prevalence of linezolid-resistant coagulase-negative Staphylococcus (CoNS) in the MD Anderson Cancer Center rose from 0.6% in 2007 to 5.5% in 2009. The aim of our study was to analyse the relationship between linezolid use and an outbreak of linezolid-resistant CoNS. PATIENTS AND METHODS: We retrospectively identified 27 infection or colonization events. Eleven isolates were available for supplemental investigation; species identification, clonal relatedness and linezolid resistance mutation analysis. The medical records of the affected patients were reviewed and linezolid utilization data were obtained from the pharmacy. RESULTS: Available isolates were confirmed as clonally related Staphylococcus epidermidis. Partial 23S rRNA gene sequencing found a G2576T mutation in all of the isolates tested. All patients received linezolid within 3 months prior to an event. Patients without a prior hospitalization had a longer time from admission to event; 29 versus 3.5 days (P = 0.002). The outbreak was preceded by a 51% increase in inpatient linezolid utilization and 64% of affected patients belonged to the leukaemia service, which had a utilization rate 3.1 times that of the other services (95% confidence interval: 2.96-3.23). CONCLUSIONS: Increased linezolid utilization preceded the appearance of a linezolid-resistant CoNS clone. Patients probably acquired the clonal strain nosocomially, given the longer time from admission to event among patients with no previous admission to the MD Anderson Cancer Center. Linezolid administration then selected this strain, since all patients received linezolid prior to an event. A linezolid utilization rate of >or=13 defined daily doses/100 patient-days was similar to that reported in two other outbreaks and may be the threshold required to generate an outbreak.
Asunto(s)
Acetamidas/uso terapéutico , Antibacterianos/uso terapéutico , Brotes de Enfermedades , Farmacorresistencia Bacteriana , Utilización de Medicamentos/estadística & datos numéricos , Oxazolidinonas/uso terapéutico , Infecciones Estafilocócicas/epidemiología , Staphylococcus epidermidis/efectos de los fármacos , Técnicas de Tipificación Bacteriana , Análisis por Conglomerados , Coagulasa/análisis , ADN Bacteriano/química , ADN Bacteriano/genética , ADN Ribosómico/química , ADN Ribosómico/genética , Genotipo , Humanos , Linezolid , Servicio de Oncología en Hospital , ARN Ribosómico 23S/genética , Estudios Retrospectivos , Análisis de Secuencia de ADN , Infecciones Estafilocócicas/microbiología , Staphylococcus epidermidis/enzimología , Staphylococcus epidermidis/aislamiento & purificación , Estados Unidos/epidemiologíaRESUMEN
5-F substitution of an aminothiazole moiety within a series of thrombopoietin receptor agonists leads to potent agents with an improved hepatic safety profile in rodent toxicology studies.
Asunto(s)
Hígado/efectos de los fármacos , Receptores de Trombopoyetina/agonistas , Tiazoles/farmacología , Animales , Hígado/metabolismo , Relación Estructura-ActividadRESUMEN
Dual inhibitors of bacterial gyrB and parE based on a 5-(2-pyrimidinyl)-imidazo[1,2-a]pyridine template exhibited MICs (microg/mL) of 0.06-64 (Sau), 0.25-64 (MRSA), 0.06-64 (Spy), 0.06-64 (Spn), and 0.03-64 (FQR Spn). Selected examples were efficacious in mouse sepsis and lung infection models at <50mg/kg (PO dosing).
Asunto(s)
Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/metabolismo , Piridinas/farmacología , Piridinas/uso terapéutico , Animales , Antibacterianos/química , Bacterias Grampositivas/efectos de los fármacos , Imidazoles/química , Imidazoles/farmacología , Imidazoles/uso terapéutico , Pulmón/efectos de los fármacos , Pulmón/microbiología , Ratones , Pruebas de Sensibilidad Microbiana , Piridinas/química , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Ratas , Sepsis/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
Recently, we disclosed a series of potent pyrimidine benzamide-based thrombopoietin receptor agonists. Unfortunately, the structural features required for the desired activity conferred physicochemical properties that were not favorable for the development of an oral agent. The physical properties of the series were improved by replacing the aminopyrimidinyl group with a piperidine-4-carboxylic acid moiety. The resulting compounds possessed favorable in vivo pharmacokinetic properties, including good bioavailability.
Asunto(s)
Benzoatos/química , Benzoatos/metabolismo , Hidrazinas/química , Hidrazinas/metabolismo , Pirazoles/química , Pirazoles/metabolismo , Receptores de Trombopoyetina/agonistas , Receptores de Trombopoyetina/metabolismo , Administración Oral , Animales , Benzoatos/administración & dosificación , Disponibilidad Biológica , Células CACO-2 , Humanos , Hidrazinas/administración & dosificación , Piperidinas/síntesis química , Piperidinas/metabolismo , Pirazinamida/análogos & derivados , Pirazinamida/síntesis química , Pirazinamida/metabolismo , Pirazoles/administración & dosificación , Pirimidinas/síntesis química , Pirimidinas/metabolismo , RatasRESUMEN
The identification of small molecule modulators of biological processes mediated via protein-protein interactions has generally proved to be a challenging endeavor. In the case of the thrombopoietin receptor (TPOr), however, a number of small molecule types have been reported to display biological activity similar to that of the agonist protein TPO. Through a detailed analysis of structure-activity relationships, X-ray crystal structures, NMR coupling constants, nuclear Overhauser effects, and computational data, we have determined the agonism-inducing conformation of one series of small molecule TPOr agonists. The relationship of this agonism-inducing conformation to that of other series of TPO receptor agonists is discussed.
Asunto(s)
Benzamidas/farmacología , Pirimidinas/farmacología , Receptores de Trombopoyetina/agonistas , Trombopoyetina , Animales , Benzamidas/química , Línea Celular , Simulación por Computador , Cristalografía por Rayos X , Espectroscopía de Resonancia Magnética , Unión Proteica , Conformación Proteica , Pirimidinas/química , Receptores de Trombopoyetina/química , Relación Estructura-Actividad , Trombopoyetina/química , Trombopoyetina/metabolismoRESUMEN
Multidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through an improved molecular understanding of drug-target interactions combined with enhanced delivery of these agents to the site of action. Herein we describe the first application of siderophore receptor-mediated drug uptake of lactivicin analogues as a strategy that enables the development of novel antibacterial agents against clinically relevant Gram-negative bacteria. We report the first crystal structures of several sideromimic conjugated compounds bound to penicillin binding proteins PBP3 and PBP1a from Pseudomonas aeruginosa and characterize the reactivity of lactivicin and ß-lactam core structures. Results from drug sensitivity studies with ß-lactamase enzymes are presented, as well as a structure-based hypothesis to reduce susceptibility to this enzyme class. Finally, mechanistic studies demonstrating that sideromimic modification alters the drug uptake process are discussed.
Asunto(s)
Bacterias Gramnegativas/metabolismo , Péptidos/metabolismo , Receptores de Superficie Celular/metabolismo , Sideróforos/metabolismo , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/enzimología , Pruebas de Sensibilidad Microbiana , Péptidos/efectos de los fármacos , Péptidos Cíclicos , beta-Lactamasas/metabolismoRESUMEN
Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli . Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.
Asunto(s)
Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Monobactamas/farmacología , Piridonas/farmacología , Animales , Antibacterianos/química , Antibacterianos/farmacocinética , Escherichia coli/efectos de los fármacos , Concentración 50 Inhibidora , Klebsiella pneumoniae/efectos de los fármacos , Masculino , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Monobactamas/química , Monobactamas/farmacocinética , Pseudomonas aeruginosa/efectos de los fármacos , Piridonas/química , Piridonas/farmacocinética , Ratas , Ratas WistarRESUMEN
We describe the investigation and control of a Klebsiella pneumoniae carbapenemase-producing K. pneumoniae outbreak in a 20-bed surgical intensive care unit during the period from January 1, 2009 through January 1, 2010. Nine patients were either colonized or infected with a monoclonal strain of K. pneumoniae. The implementation of a bundle of interventions on July 2009 successfully controlled the further horizontal spread of this organism.
Asunto(s)
Antibacterianos/uso terapéutico , Proteínas Bacterianas/biosíntesis , Cuidados Críticos , Brotes de Enfermedades/prevención & control , Control de Infecciones/métodos , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae/efectos de los fármacos , beta-Lactamasas/biosíntesis , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Femenino , Florida/epidemiología , Hospitales de Enseñanza , Humanos , Infecciones por Klebsiella/epidemiología , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/enzimología , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/aislamiento & purificación , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Resultado del Tratamiento , beta-Lactamasas/genéticaRESUMEN
There is a critical need for safer and more convenient treatments for organ transplant rejection and autoimmune disorders such as rheumatoid arthritis. Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells and are involved in the signaling of multiple cytokines important for various T cell functions. Blockade of the JAK1/JAK3-STAT pathway with a small molecule was anticipated to provide therapeutic immunosuppression/immunomodulation. The Pfizer compound library was screened against the catalytic domain of JAK3 resulting in the identification of a pyrrolopyrimidine-based series of inhibitors represented by CP-352,664 (2a). Synthetic analogues of 2a were screened against the JAK enzymes and evaluated in an IL-2 induced T cell blast proliferation assay. Select compounds were evaluated in rodent efficacy models of allograft rejection and destructive inflammatory arthritis. Optimization within this chemical series led to identification of CP-690,550 1, a potential first-in-class JAK inhibitor for treatment of autoimmune diseases and organ transplant rejection.
Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Rechazo de Injerto/tratamiento farmacológico , Quinasas Janus/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirroles/síntesis química , Animales , Proteínas Sanguíneas/metabolismo , Células CACO-2 , Línea Celular Tumoral , Permeabilidad de la Membrana Celular , Proliferación Celular/efectos de los fármacos , Monoterpenos Ciclohexánicos , Perros , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Humanos , Técnicas In Vitro , Activación de Linfocitos/efectos de los fármacos , Macaca fascicularis , Masculino , Modelos Moleculares , Monoterpenos/síntesis química , Monoterpenos/farmacocinética , Monoterpenos/farmacología , Piperidinas/síntesis química , Piperidinas/farmacocinética , Piperidinas/farmacología , Unión Proteica , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Distribución TisularRESUMEN
A series of pyrimidine benzamide-based thrombopoietin receptor agonists is described. The lead molecule contains a 2-amino-5-unsubstituted thiazole, a group that has been associated with idiosyncratic toxicity. The potential for metabolic oxidation at C-5 of the thiazole, the likely source of toxic metabolites, was removed by substitution at C-5 or by replacing the thiazole with a thiadiazole. Potency in the series was improved by modifying the substituents on the pyrimidine and/or on the thiazole or thiadiazole pendant aryl ring. In vivo examination revealed that compounds from the series are not highly bioavailable. This is attributed to low solubility and poor permeability.
Asunto(s)
Benzamidas/síntesis química , Benzamidas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Receptores de Trombopoyetina/agonistas , Antígenos CD34/metabolismo , Benzamidas/farmacocinética , Diferenciación Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Fenómenos Químicos , Química Física , Simulación por Computador , Reacciones Cruzadas , Evaluación Preclínica de Medicamentos , Humanos , Peso Molecular , Pirimidinas/farmacocinética , Solubilidad , Relación Estructura-ActividadRESUMEN
Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.