Identification of CH2-linked quinolone-aminopyrimidine hybrids as potent anti-MRSA agents: Low resistance potential and lack of cross-resistance with fluoroquinolone antibiotics.

The structural optimization of B14, an antibacterial agent we previously obtained, has led to the discovery of a new class of CH2-linked quinolone-aminopyrimidine hybrids with potent anti-MRSA activities. Surprisingly, the hybrids lacking a C-6 fluoro atom at the quinolone nucleus showed equal or even stronger anti-MRSA activities than their corresponding 6-fluoro counterparts, despite the well-established structure-activity relationships (SARs) indicating that the 6-fluoro substituent enhances the antibacterial activity in conventional fluoroquinolone antibiotics. Moreover, these new hybrids, albeit structurally related to conventional fluoroquinolones, showed no cross-resistance with fluoroquinolone drugs. The most active compound, 15m, exhibited excellent activities with a MIC value of 0.39 µg/mL against both fluoroquinolone-sensitive strain USA500 and -resistant MRSA isolate Mu50. Further resistance development studies indicated MRSA is unlikely to acquire resistance against 15m. Moreover, 15m displayed favorable in vivo half-life and safety profiles. These findings suggest a rationale for further evolution of quinolone antibiotics with a high barrier to resistance.

Generación in vitro de mutantes de Klebsiella pneumoniae tras exposición a fluoroquinolonas. Relación con la presencia de betalactamasas de espectro extendido / In vitro generation of mutants of Klebsiella pneumoniae following exposure to fluorquinolones. Relationship with the presence of extended spectrum betalactamases

Con objeto de aportar datos que ayuden a explicar laasociación entre producción de betalactamasas de espectroextendido (BLEE) y resistencia a fluoroquinolonas en Klebsiellapneumoniae, hemos desarrollado un modelo in vitro deexposición a concentraciones subinhibitorias de varios fármacosde esta familia (ciprofloxacino, levofloxacino y moxifloxacino)con dos cepas, una productora de BLEE.Nuestros datos muestran que aparecen mutantes consensibilidad disminuida a fluoroquinolonas en los dos casos,pero más precozmente en cepas productoras de BLEE (13,3frente a 14,4 días), sobre todo tras exposición a ciprofloxacino(12,5 frente a 14,9 días para levofloxacino y 14,2 díaspara moxifloxacino).Por tanto, nuestros datos ayudan a explicar la mayorresistencia a fluoroquinolonas en cepas productoras de BLEEy confirman la necesidad de administrar dosis adecuadas defluoroquinolonas, especialmente de ciprofloxacino, con objetode prevenir la aparición de mutantes resistentes, sobretodo si la cepa es productora de BLEE (AU)

In order to provide data that may help to explain therelationship between production of extended spectrumbetalactamases and fluorquinolone resistance in Klebsie-lla pneumoniae, we have developed an in vitro model ofexposure to sub-inhibitory concentrations of variousfluorquinolones (ciprofloxacin, levofloxacin and moxifloxacin)in two strains, one of which is a producer ofextended spectrum betalactamases (ESBL).Our data show that mutants with reduced fluorquinolonesusceptibility appear in both cases, but that theyappear earlier in ESBL-producing strains (13.3 days versus14.4 days), especially following exposure to ciprofloxacin(12.5 days versus 14.9 days for levofloxacin and14.2 days for moxifloxacin).Therefore, our data help explain the greater fluorquinoloneresistance in ESBL-producing strains and confirmthe need to administer the correct doses of fluoroquinolones,especially in the case of ciprofloxacin, in order toprevent the emergence of resistant mutants. This is particularlyimportant if the strain is an ESBL-producer (AU)

Relación estructura-fotoestabilidad u fototoxicidad de fluoroquinolonas / Structure-photostability and phototoxicity relationship in fluoroquinolones

Las quinolonas constituyen una familia de antibióticos de amplio uso en la actualidad, debido a su gran eficacia clínica en el tratamiento de infecciones del tracto respiratorio, urinario, tejidos blandos y enfermedades de transmisión sexual. De acuerdo a su estructura base se pueden clasificar en quinolonas naftiridínicas (enoxacino y ácido nalidíxico), quinolínicas (ciprofloxacino, norfloxacino, ácido oxolínico, rosoxacino) y pirimido-pirimidinicas (ácido pipemídico). Las quinolonas se caracterizan por presentar reacciones de fotosensibilidad y fotolabilidad. El ácido nalidíxico, quinolona de primera generación, presenta reacciones de fototoxicidad, evaluadas en el modelo del glóbulo rojo y en cultivos celulares. El ácido nalidíxico, exento del sustituyente piperazínico presenta una fotolabilidad disminuida. Las fluoroquinolonas, a diferencia del ácido nalidíxico, presentan un anillo piperazínico o metil piperazínico en posición 7, incorporado con el fin de mejorar las propiedades antibacterianas. En este trabajo se investiga la influencia del anillo piperazínico en posición 7 sobre la fotolabilidad y fototoxicidad, demostrándose que las fluoroquinolonas que poseen este sustituyente presentan una fotolabilidad aumentada y una fototoxicidad disminuída, en relación a quinolonas carentes de éste grupo. Es probable que la fotodegradación de quinolonas transcurra mediante un mecanismo radicalario, con la pérdida del grupo carboxílico

Quinolones constitute a large class of synthetic antimicrobial agents that are highly effective in the treatment of respiratory, urinary, sexually transmitted diseases and soft tissue infection. In agreement with his structure the quinolones can be classified into naftaridines (enoxacin and nalidixic acid), quinolines (ciprofloxacin, norfloxacin, oxolinic acid, roxosacin) and pyrid-pyrimidin (pipemidic acid). Some quinolones may undergo photodegradation reactions. On the other hand, quinolones can induce cutaneous photosensitivity reactions.and photolability as well. Nalidixic acid, a first quinolone generation, may undergo phototoxic effects on the red blood cells and in cell culture. Nalidixic acid, which has not the piperazine group in position 7, exhibit a moderated photolability. The fluoroquinolones as oppossed to nalidixic acid have a piperazine ring in position 7. We investigated the influence of the piperazine ring on the phototoxicity and photolability of several quinolones. We demonstrated that the fluoroquinolones with piperazinic group present higher photolability and less phototoxicity .It is possible that the photodegradation of quinolones takes place through a radical pathway, with the loss of a carboxylic acid group