RESUMO
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.
Assuntos
Burkholderia pseudomallei , Burkholderia pseudomallei/genética , Farmacorresistência Bacteriana Múltipla , Antibacterianos/farmacologia , Fluoroquinolonas/farmacologia , Testes de Sensibilidade Microbiana , Ciprofloxacina/farmacologiaRESUMO
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.
Assuntos
Antibacterianos/farmacologia , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , Quinolinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , DNA Topoisomerase IV/metabolismo , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/metabolismo , Cobaias , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Streptococcus pyogenes/efeitos dos fármacos , Streptococcus pyogenes/enzimologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/químicaRESUMO
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).
Assuntos
Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Teicoplanina/análogos & derivados , Daptomicina/farmacologia , Farmacorresistência Bacteriana Múltipla , Monitoramento Epidemiológico , Humanos , Linezolida/farmacologia , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Testes de Sensibilidade Microbiana , Minociclina/análogos & derivados , Minociclina/farmacologia , Teicoplanina/farmacologia , Tigeciclina , Estados UnidosRESUMO
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.
Assuntos
Bactérias Gram-Negativas/metabolismo , Peptídeos/metabolismo , Receptores de Superfície Celular/metabolismo , Sideróforos/metabolismo , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/enzimologia , Testes de Sensibilidade Microbiana , Peptídeos/efeitos dos fármacos , Peptídeos Cíclicos , beta-Lactamases/metabolismoRESUMO
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.
Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Monobactamas/farmacologia , Piridonas/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Escherichia coli/efeitos dos fármacos , Concentração Inibidora 50 , Klebsiella pneumoniae/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Estrutura Molecular , Monobactamas/química , Monobactamas/farmacocinética , Pseudomonas aeruginosa/efeitos dos fármacos , Piridonas/química , Piridonas/farmacocinética , Ratos , Ratos WistarRESUMO
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.
Assuntos
Antibacterianos/farmacologia , DNA Topoisomerase IV/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Quinolinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Inibidores da Topoisomerase II , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , DNA Girase/metabolismo , DNA Topoisomerase IV/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Quinolinas/administração & dosagem , Quinolinas/química , Ratos , Staphylococcus aureus/enzimologia , Streptococcus pneumoniae/enzimologia , Relação Estrutura-AtividadeRESUMO
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).
Assuntos
Antibacterianos/química , Eritromicina/análogos & derivados , Compostos de Metilureia/química , Staphylococcus/isolamento & purificação , Streptococcus/isolamento & purificação , Antibacterianos/síntese química , Sítios de Ligação , Cristalografia por Raios X , Deinococcus/metabolismo , Farmacorresistência Bacteriana , Eritromicina/síntese química , Escherichia coli/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Terciária de Proteína , Pirrolidinas/química , Subunidades Ribossômicas Maiores de Bactérias/química , Subunidades Ribossômicas Maiores de Bactérias/metabolismo , Staphylococcus/efeitos dos fármacos , Streptococcus/efeitos dos fármacosRESUMO
Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MDR Gram-negative pathogens are described.
Assuntos
Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Monobactamas/farmacologia , Animais , Sítios de Ligação/efeitos dos fármacos , Proteínas Sanguíneas/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Monobactamas/síntese química , Monobactamas/química , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Rejeição de Enxerto/tratamento farmacológico , Janus Quinases/antagonistas & inibidores , Pirimidinas/síntese química , Pirróis/síntese química , Animais , Proteínas Sanguíneas/metabolismo , Células CACO-2 , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Proliferação de Células/efeitos dos fármacos , Monoterpenos Cicloexânicos , Cães , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Técnicas In Vitro , Ativação Linfocitária/efeitos dos fármacos , Macaca fascicularis , Masculino , Modelos Moleculares , Monoterpenos/síntese química , Monoterpenos/farmacocinética , Monoterpenos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ligação Proteica , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Distribuição TecidualRESUMO
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.
Assuntos
Acetamidas/farmacologia , Antibacterianos/farmacologia , Surtos de Doenças , Farmacorresistência Bacteriana , Oxazolidinonas/farmacologia , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus epidermidis/efeitos dos fármacos , Proteínas de Bactérias/genética , Técnicas de Tipagem Bacteriana , Impressões Digitais de DNA , DNA Bacteriano/genética , Eletroforese em Gel de Campo Pulsado , Genótipo , Hospitais , Humanos , Linezolida , Ohio/epidemiologia , Staphylococcus epidermidis/isolamento & purificaçãoRESUMO
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.
Assuntos
Antibacterianos/uso terapêutico , Proteínas de Bactérias/biossíntese , Cuidados Críticos , Surtos de Doenças/prevenção & controle , Controle de Infecções/métodos , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/efeitos dos fármacos , beta-Lactamases/biossíntese , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Feminino , Florida/epidemiologia , Hospitais de Ensino , Humanos , Infecções por Klebsiella/epidemiologia , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/enzimologia , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/isolamento & purificação , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Resultado do Tratamento , beta-Lactamases/genéticaRESUMO
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.
Assuntos
Fígado/efeitos dos fármacos , Receptores de Trombopoetina/agonistas , Tiazóis/farmacologia , Animais , Fígado/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Acetamidas/uso terapêutico , Antibacterianos/uso terapêutico , Surtos de Doenças , Farmacorresistência Bacteriana , Uso de Medicamentos/estatística & dados numéricos , Oxazolidinonas/uso terapêutico , Infecções Estafilocócicas/epidemiologia , Staphylococcus epidermidis/efeitos dos fármacos , Técnicas de Tipagem Bacteriana , Análise por Conglomerados , Coagulase/análise , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Genótipo , Humanos , Linezolida , Serviço Hospitalar de Oncologia , RNA Ribossômico 23S/genética , Estudos Retrospectivos , Análise de Sequência de DNA , Infecções Estafilocócicas/microbiologia , Staphylococcus epidermidis/enzimologia , Staphylococcus epidermidis/isolamento & purificação , Estados Unidos/epidemiologiaRESUMO
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).
Assuntos
Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , DNA Girase/metabolismo , DNA Topoisomerase IV/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Animais , Antibacterianos/química , Bactérias Gram-Positivas/efeitos dos fármacos , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Piridinas/química , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ratos , Sepse/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Benzoatos/química , Benzoatos/metabolismo , Hidrazinas/química , Hidrazinas/metabolismo , Pirazóis/química , Pirazóis/metabolismo , Receptores de Trombopoetina/agonistas , Receptores de Trombopoetina/metabolismo , Administração Oral , Animais , Benzoatos/administração & dosagem , Disponibilidade Biológica , Células CACO-2 , Humanos , Hidrazinas/administração & dosagem , Piperidinas/síntese química , Piperidinas/metabolismo , Pirazinamida/análogos & derivados , Pirazinamida/síntese química , Pirazinamida/metabolismo , Pirazóis/administração & dosagem , Pirimidinas/síntese química , Pirimidinas/metabolismo , RatosRESUMO
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.
Assuntos
Benzamidas/farmacologia , Pirimidinas/farmacologia , Receptores de Trombopoetina/agonistas , Trombopoetina , Animais , Benzamidas/química , Linhagem Celular , Simulação por Computador , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Ligação Proteica , Conformação Proteica , Pirimidinas/química , Receptores de Trombopoetina/química , Relação Estrutura-Atividade , Trombopoetina/química , Trombopoetina/metabolismoRESUMO
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.
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de Trombopoetina/agonistas , Antígenos CD34/metabolismo , Benzamidas/farmacocinética , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Fenômenos Químicos , Físico-Química , Simulação por Computador , Reações Cruzadas , Avaliação Pré-Clínica de Medicamentos , Humanos , Peso Molecular , Pirimidinas/farmacocinética , Solubilidade , Relação Estrutura-AtividadeRESUMO
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.