RESUMEN
Novel antibacterial fluoroquinolone agents bearing a 4-alkylidenylpiperidine 7-position substituent are active against quinolone-susceptible and quinolone-resistant gram-positive bacteria, including Streptococcus pneumoniae and MRSA. Analogs 22b, 23c, and 24 demonstrated superior in vitro and in vivo efficacy to ciprofloxacin against these cocci.
Asunto(s)
Antibacterianos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Quinolonas/farmacología , Inhibidores de Topoisomerasa/farmacología , HumanosRESUMEN
JNJ-Q2, a novel fluorinated 4-quinolone, was evaluated for its antibacterial potency by broth and agar microdilution MIC methods in studies focused on skin and respiratory tract pathogens, including strains exhibiting contemporary fluoroquinolone resistance phenotypes. Against a set of 118 recent clinical isolates of Streptococcus pneumoniae, including fluoroquinolone-resistant variants bearing multiple DNA topoisomerase target mutations, an MIC(90) value for JNJ-Q2 of 0.12 microg/ml was determined, indicating that it was 32-fold more potent than moxifloxacin. Against a collection of 345 recently collected methicillin-resistant Staphylococcus aureus (MRSA) isolates, including 256 ciprofloxacin-resistant strains, the JNJ-Q2 MIC(90) value was 0.25 microg/ml, similarly indicating that it was 32-fold more potent than moxifloxacin. The activities of JNJ-Q2 against Gram-negative pathogens were generally comparable to those of moxifloxacin. In further studies, JNJ-Q2 exhibited bactericidal activities at 2x and 4x MIC levels against clinical isolates of S. pneumoniae and MRSA with various fluoroquinolone susceptibilities, and its activities were enhanced over those of moxifloxacin. In these studies, the activity exhibited against strains bearing gyrA, parC, or gyrA plus parC mutations was indicative of the relatively balanced (equipotent) activity of JNJ-Q2 against the DNA topoisomerase target enzymes. Finally, determination of the relative rates or frequencies of the spontaneous development of resistance to JNJ-Q2 at 2x and 4x MICs in S. pneumoniae, MRSA, and Escherichia coli were indicative of a lower potential for resistance development than that for current fluoroquinolones. In conclusion, JNJ-Q2 exhibits a range of antibacterial activities in vitro that is supportive of its further evaluation as a potential new agent for the treatment of skin and respiratory tract infections.
Asunto(s)
Antibacterianos/farmacología , Fluoroquinolonas/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Antibacterianos/química , Ciprofloxacina/farmacología , Diseño de Fármacos , Farmacorresistencia Bacteriana/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Fluoroquinolonas/químicaRESUMEN
A novel series of 7-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl) quinolones has been designed and synthesized in which the heterocyclic side chain is attached to the quinolone core through a carbon-carbon linkage. The antibacterial activity of the compounds was determined against a panel of Gram-positive and Gram-negative pathogens. Compounds 1b and 1e, bearing an 8-methoxy group as well as unsubstituted and (3S)-methyl substituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl side chains, respectively, demonstrated notable activity against ciprofloxacin-resistant clinical isolates of Streptococcus pneumoniae.
Asunto(s)
Antibacterianos/síntesis química , Quinolonas/síntesis química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Quinolonas/química , Quinolonas/farmacología , Relación Estructura-ActividadRESUMEN
MurF catalyzes the last cytoplasmic step of bacterial cell wall synthesis and is essential for bacterial survival. Our previous studies used a pharmacophore model of a MurF inhibitor to identify additional inhibitors with improved properties. We now present the characterization of two such inhibitors, the diarylquinolines DQ1 and DQ2. DQ1 inhibited Escherichia coli MurF (50% inhibitory concentration, 24 microM) and had modest activity (MICs, 8 to 16 microg/ml) against lipopolysaccharide (LPS)-defective E. coli and wild-type E. coli rendered permeable with polymyxin B nonapeptide. DQ2 additionally displayed activity against gram-positive bacteria (MICs, 8 to 16 microg/ml), including methicillin (meticillin)-susceptible and -resistant Staphylococcus aureus isolates and vancomycin-susceptible and -resistant Enterococcus faecalis and Enterococcus faecium isolates. Treatment of LPS-defective E. coli cells with >or=2x MIC of DQ1 resulted in a 75-fold-greater accumulation of the MurF substrate compared to the control, a 70% decline in the amount of the MurF product, and eventual cell lysis, consistent with the inhibition of MurF within bacteria. DQ2 treatment of S. aureus resulted in similar effects on the MurF substrate and product quantities. At lower levels of DQ1 (Asunto(s)
Antibacterianos/farmacología
, Bacterias/efectos de los fármacos
, Inhibidores Enzimáticos/farmacología
, Péptido Sintasas/antagonistas & inhibidores
, Quinolinas/farmacología
, Antibacterianos/química
, Enterococcus faecalis/efectos de los fármacos
, Enterococcus faecium/efectos de los fármacos
, Inhibidores Enzimáticos/química
, Escherichia coli/efectos de los fármacos
, Pruebas de Sensibilidad Microbiana
, Estructura Molecular
, Péptido Sintasas/genética
, Péptido Sintasas/fisiología
, Quinolinas/química
, Staphylococcus aureus/efectos de los fármacos
RESUMEN
Ceftobiprole, an anti-methicillin-resistant Staphylococcus aureus broad-spectrum cephalosporin, has activity (MIC for 50% of strains tested, < or =4 microg/ml) against many Pseudomonas aeruginosa strains. A common mechanism of P. aeruginosa resistance to beta-lactams, including cefepime and ceftazidime, is efflux via increased expression of Mex pumps, especially MexAB. MexXY has differential substrate specificity, recognizing cefepime but not ceftazidime. In ceftobiprole clinical studies, paired isolates of P. aeruginosa from four subjects demonstrated ceftobiprole MICs of 2 to 4 microg/ml at baseline but 16 microg/ml posttreatment, unrelated to beta-lactamase levels. Within each pair, the level of mexXY RNA, but not mexAB, mexCD, and mexEF, increased by an average of 50-fold from baseline to posttreatment isolates. Sequencing of the negative regulatory gene mexZ indicated that each posttreatment isolate contained a mutation not present at baseline. mexXY expression as a primary ceftobiprole and cefepime resistance mechanism was further examined in isogenic pairs by using cloned mexXY and mexZ. Expression of cloned mexXY in strain PAO1 or in a baseline isolate increased the ceftobiprole MIC to that for the posttreatment isolate. In contrast, in posttreatment isolates, lowering mexXY expression via introduction of cloned mexZ decreased the ceftobiprole MIC to that for the baseline isolates. Similar changes were observed for cefepime. A spontaneous mutant selectively overexpressing mexXY displayed a fourfold elevation in its ceftobiprole MIC, while overexpression of mexAB, -CD, and -EF had a minimal effect. These data indicate that ceftobiprole, like cefepime, is an atypical beta-lactam that is a substrate for the MexXY efflux pump in P. aeruginosa.
Asunto(s)
Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Cefalosporinas/farmacología , Farmacorresistencia Bacteriana/genética , Expresión Génica , Pseudomonas aeruginosa/efectos de los fármacos , Proteínas Bacterianas/genética , Proteínas Bacterianas/fisiología , Cefepima , Electroforesis en Gel de Campo Pulsado , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
MurF is an essential enzyme of bacterial cell wall biosynthesis. Few MurF inhibitors have been reported, and none have displayed measurable antibacterial activity. Through the use of a MurF binding assay, a series of 8-hydroxyquinolines that bound to the Escherichia coli enzyme and inhibited its activity was identified. To derive additional chemotypes lacking 8-hydroxyquinoline, a known chelating moiety, a pharmacophore model was constructed from the series and used to select compounds for testing in the MurF binding and enzymatic inhibition assays. Whereas the original diverse library yielded 0.01% positive compounds in the binding assay, of which 6% inhibited MurF enzymatic activity, the pharmacophore-selected set yielded 14% positive compounds, of which 37% inhibited the enzyme, suggesting that the model enriched for compounds with affinity to MurF. A 4-phenylpiperidine (4-PP) derivative identified by this process displayed antibacterial activity (MIC of 8 microg/ml against permeable E. coli) including cell lysis and a 5-log(10)-unit decrease in CFU. Importantly, treatment of E. coli with 4-PP resulted in a 15-fold increase in the amount of the MurF UDP-MurNAc-tripeptide substrate, and a 50% reduction in the amount of the MurF UDP-MurNAc-pentapeptide product, consistent with inhibition of the MurF enzyme within bacterial cells. Thus, 4-PP is the first reported inhibitor of the MurF enzyme that may contribute to antibacterial activity by interfering with cell wall biosynthesis.
Asunto(s)
Pared Celular/metabolismo , Proteínas de Escherichia coli/antagonistas & inhibidores , Escherichia coli/efectos de los fármacos , Péptido Sintasas/antagonistas & inhibidores , Cicloserina/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Modelos Moleculares , Estructura Molecular , Oxiquinolina/química , Oxiquinolina/farmacología , Péptido Sintasas/metabolismo , Factores de TiempoRESUMEN
A series of 3-keto-6-O-carbamoyl-11,12-cyclic thiocarbamate erythromycin A derivatives has been synthesized. The best compounds in this series possess potent in vitro antibacterial activity against erythromycin-susceptible and erythromycin-resistant bacteria.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Eritromicina/síntesis química , Eritromicina/farmacología , Eritromicina/análogos & derivados , Pruebas de Sensibilidad Microbiana , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacosRESUMEN
RWJ-416457, an investigational pyrrolopyrazolyl-substituted oxazolidinone, inhibited the growth of linezolid-susceptible staphylococci, enterococci, and streptococci at concentrations of < or =4 microg/ml, generally exhibiting two- to fourfold-greater potency than that of linezolid. Time-kill studies demonstrated bacteriostatic effects for both RWJ-416457 and linezolid.
Asunto(s)
Antibacterianos/farmacología , Oxazolidinonas/farmacología , Acetamidas/química , Antibacterianos/química , Farmacorresistencia Bacteriana , Enterococcus/efectos de los fármacos , Linezolid , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Oxazolidinonas/química , Staphylococcus/efectos de los fármacos , Streptococcus/efectos de los fármacosRESUMEN
A novel series of ketolides containing heteroaryl groups that are linked to the erythronolide ring via a C6-carbazate functionality has been successfully synthesized. Careful modulation of the heteroaryl groups, the length and degree of saturation of the C6-carbazate linker, and the substituents present on each of the carbazate nitrogens led to compounds with potent activity against key bacterial respiratory pathogens. The best analogs of this series had in vitro and in vivo (sc dosing) profiles that were comparable to telithromycin.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Hidrazinas , Cetólidos/síntesis química , Cetólidos/farmacología , Staphylococcus/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
A series of pyrrolopyridine-substituted oxazolidinones containing various C-5 acetamide isosteres was synthesized and the structure-antibacterial activity relationships determined against a representative panel of susceptible and resistant Gram-positive bacteria.
Asunto(s)
Acetamidas/química , Antibacterianos/síntesis química , Antibacterianos/farmacología , Oxazolidinonas/química , Oxazolidinonas/farmacología , Piridinas/química , Antibacterianos/química , Enterococcus/efectos de los fármacos , Linezolid , Estructura Molecular , Oxazolidinonas/síntesis química , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A new series of erythromycin A derivatives, the 6-O-heteroarylcarbamoyl-11,12-lactoketolides, with activity against macrolide-resistant streptococci, are described. Structurally, these macrolide antibiotics are characterized by a heteroaryl side chain attached to the macrolactone core through a carbamate linkage at the C6 position, as well as 11,12-gamma-lactone and 3-keto functionalities. The synthesis and antibacterial activity of this new series of ketolides are discussed.
Asunto(s)
Antibacterianos/síntesis química , Cetólidos/síntesis química , Cetólidos/farmacología , Antibacterianos/farmacología , Haemophilus influenzae/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Streptococcus pneumoniae/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A series of 3-O-acyl-6-O-carbamoyl erythromycin A derivatives has been synthesized. Several functional groups were identified as the optimal C3-substituents, and the best compounds in this series possess potent in vitro antibacterial activity against erythromycin-susceptible and erythromycin-resistant bacteria.
Asunto(s)
Antibacterianos , Bacterias/efectos de los fármacos , Eritromicina/análogos & derivados , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Eritromicina/síntesis química , Eritromicina/farmacología , Cetólidos/farmacología , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A new series of antibacterial ketolides is reported, which features the use of a C-6 carbamate for tethering the arylalkyl sidechain to the macrolide core. The best members of this series display in vitro and in vivo activity comparable to telithromycin. Partial epimerization at C-2, unobserved in previously reported ketolides, was noted for this series.
Asunto(s)
Antibacterianos/síntesis química , Carbamatos/síntesis química , Cetólidos/síntesis química , Administración Oral , Animales , Antibacterianos/administración & dosificación , Carbamatos/administración & dosificación , Femenino , Cetólidos/administración & dosificación , Ratones , Pruebas de Sensibilidad Microbiana/estadística & datos numéricosRESUMEN
A series of oxazolidinone antibacterial agents containing a 5-substituted isoxazol-3-yl moiety were synthesized via a nitrile oxide [3+2] dipolar cycloaddition reaction. These compounds were screened against a panel of susceptible and resistant Gram-positive organisms. Several analogs from this series were comparable to or more potent than linezolid in vitro.
Asunto(s)
Antibacterianos/síntesis química , Isoxazoles/síntesis química , Oxazolidinonas/síntesis química , Animales , Antibacterianos/farmacología , Evaluación Preclínica de Medicamentos/métodos , Femenino , Isoxazoles/farmacología , Ratones , Pruebas de Sensibilidad Microbiana/métodos , Oxazolidinonas/farmacologíaRESUMEN
A novel series of oxazolidinones containing a pyrroloaryl substituent was synthesized and screened against a representative panel of susceptible and resistant Gram-positive bacteria. Several members of this series were found to have antibacterial activity comparable to or better than linezolid.
Asunto(s)
Acetamidas/síntesis química , Acetamidas/farmacología , Antibacterianos/síntesis química , Antibacterianos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacología , Acetamidas/química , Antibacterianos/química , Linezolid , Pruebas de Sensibilidad Microbiana , Oxazolidinonas/química , Relación Estructura-ActividadRESUMEN
Oxazolidinone antibacterial agents, where the morpholino group of linezolid was replaced with an N-substituted piperidinyloxy moiety, were synthesized and shown to be active against a variety of resistant and susceptible Gram-positive organisms. The functionality attached to the piperidine nitrogen was varied extensively to determine the SAR for this series. One of the most potent compounds, 11, showed in vivo efficacy upon subcutaneous administration in a Staphylococcus aureus Smith murine systemic infection.