ABSTRACT
A new class of benzoxaborole ß-lactamase inhibitors were designed and synthesized. 6-Aryloxy benzoxaborole 22 inhibited AmpC P99 and CMY-2 with K(i) values in the low nanomolar range. Compound 22 restored antibacterial activity of ceftazidime against Enterobacter cloacae P99 expressing AmpC, a class C ß-lactamase enzyme. The SAR around the arylbenzoxaboroles, which included the influence of linker and substitutions was also established.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Benzoxazoles/chemistry , Boron Compounds/chemistry , Enzyme Inhibitors/chemical synthesis , Pyrazines/chemical synthesis , beta-Lactamase Inhibitors , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Boron Compounds/chemical synthesis , Boron Compounds/pharmacology , Enterobacter cloacae/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Microbial Sensitivity Tests , Pyrazines/chemistry , Pyrazines/pharmacology , Structure-Activity Relationship , beta-Lactamases/metabolismABSTRACT
The Junction Creek watershed, located in Sudbury, ON, Canada receives effluent from three metal mine wastewater treatment plants, as well as a municipal wastewater (MWW) discharge. Effects on fish have been documented within the creek (decreased egg size and increased metal body burdens). It has been difficult to identify the cause of the effects observed due to the confounded nature of the creek. The objectives of this investigation were to assess the: (1) effects of a mine effluent and municipal wastewater (CCMWW) mixture on fathead minnow (FHM; Pimephales promelas) reproduction in an on-site artificial stream and (2) importance of food (Chironomus tentans) as a source of exposure using a trophic-transfer system. Exposures to CCMWW through the water significantly decreased egg production and spawning events. Exposure through food and water using the trophic-transfer system significantly increased egg production and spawning events. Embryos produced in the trophic-transfer system showed similar hatching success but increased incidence and severity of deformities after CCMWW exposure. We concluded that effects of CCMWW on FHM were more apparent when exposed through the water. Exposure through food and water may have reduced effluent toxicity, possibly due to increased nutrients and organic matter, which may have reduced metal bioavailability. More detailed examination of metal concentrations in the sediment, water column, prey (C. tentans) and FHM tissues is recommended to better understand the toxicokinetics of potential causative compounds within the different aquatic compartments when conducting exposures through different pathways.
