Fosfomycin, from susceptibility to resistance: Impact of the new guidelines on breakpoints.

The fosfomycin breakpoint using the disc diffusion method (DDM) changed in the 2019 CA-SFM/EUCAST guidelines v2 (24mm versus 19mm). We assessed its impact on categorization of Enterobacterales recovered from urine samples in emergency departments. A total of 7749 and 2348 strains were tested using the DDM and the broth microdilution method (BMD), respectively. The DDM with the 19-mm breakpoint was in accordance with the BMD. Using the 24-mm breakpoint, the overall rate of fosfomycin resistance in Enterobacterales increased by three-fold (5.6% vs 18.1%, P<0.01) and reached 2.8% and 86.5% in E. coli and K. pneumoniae, respectively. French guidelines for the management of community-acquired UTI remain appropriate. The accuracy of the methods for routine fosfomycin susceptibility testing should be assessed. The role of fosfomycin in the treatment of documented CA-UTI due to Enterobacterales other than E. coli should be evaluated considering its rate of resistance and recent data reporting low accuracy.

Genetic and Biochemical Characterization of OXA-535, a Distantly Related OXA-48-Like ß-Lactamase.

OXA-535 is a chromosome-encoded carbapenemase of Shewanella bicestrii JAB-1 that shares only 91.3% amino acid sequence identity with OXA-48. Catalytic efficiencies are similar to those of OXA-48 for most ß-lactams, except for ertapenem, where a 2,000-fold-higher efficiency was observed with OXA-535. OXA-535 and OXA-436, a plasmid-encoded variant of OXA-535 differing by three amino acids, form a novel cluster of distantly related OXA-48-like carbapenemases. Comparison of blaOXA-535 and blaOXA-436 genetic environments suggests that an ISCR1 may be responsible for blaOXA-436 gene mobilization from the chromosome of Shewanella spp. to plasmids.

Rapid prey evolution can alter the structure of predator-prey communities.

Although microevolution has been shown to play an important role in pairwise antagonistic species interactions, its importance in more complex communities has received little attention. Here, we used two Pseudomonas fluorescens prey bacterial strains (SBW25 and F113) and Tetrahymena thermophila protist predator to study how rapid evolution affects the structuring of predator-prey communities. Both bacterial strains coexisted in the absence of predation, and F113 was competitively excluded in the presence of both SBW25 and predator during the 24-day experiment, an initially surprising result given that F113 was originally poorer at growing, but more resistant to predation. However, this can be explained by SBW25 evolving greater antipredatory defence with a lower growth cost than F113. These results show that rapid prey evolution can alter the structure of predator-prey communities, having different effects depending on the initial composition of the evolving community. From a more applied perspective, our results suggest that the effectiveness of biocontrol bacteria, such as F113, could be weaker in communities characterized by intense bacterial competition and protist predation.

Genotypic richness and dissimilarity opposingly affect ecosystem functioning.

Biodiversity is an essential determinant of ecosystem functioning. Numerous studies described positive effects of diversity on the functioning of communities arising from complementary resource use and facilitation. However, high biodiversity may also increase competitive interactions, fostering antagonism and negatively affecting community performance. Using experimental bacterial communities we differentiated diversity effects based on genotypic richness and dissimilarity. We show that these diversity characteristics have opposite effects on ecosystem functioning. Genotypic dissimilarity governed complementary resource use, improving ecosystem functioning in complex resource environments. Contrastingly, genotypic richness drove allelopathic interactions, mostly reducing ecosystem functioning. The net biodiversity effect on community performance resulted from the interplay between the genetic structure of the community and resource complexity. These results demonstrate that increasing richness, without concomitantly increasing dissimilarity, can decrease ecosystem functioning in simple environments due to antagonistic interactions, an effect insufficiently considered so far in mechanistic models of the biodiversity-ecosystem functioning relationship.

The mitochondrial complex I inhibitor annonacin is toxic to mesencephalic dopaminergic neurons by impairment of energy metabolism.

The death of dopaminergic neurons induced by systemic administration of mitochondrial respiratory chain complex I inhibitors such as 1-methyl-4-phenylpyridinium (MPP(+); given as the prodrug 1-methyl-1,2,3,6-tetrahydropyridine) or the pesticide rotenone have raised the question as to whether this family of compounds are the cause of some forms of Parkinsonism. We have examined the neurotoxic potential of another complex I inhibitor, annonacin, the major acetogenin of Annona muricata (soursop), a tropical plant suspected to be the cause of an atypical form of Parkinson disease in the French West Indies (Guadeloupe). When added to mesencephalic cultures for 24 h, annonacin was much more potent than MPP(+) (effective concentration [EC(50)]=0.018 versus 1.9 microM) and as effective as rotenone (EC(50)=0.034 microM) in killing dopaminergic neurons. The uptake of [(3)H]-dopamine used as an index of dopaminergic cell function was similarly reduced. Toxic effects were seen at lower concentrations when the incubation time was extended by several days whereas withdrawal of the toxin after a short-term exposure (<6 h) arrested cell demise. Unlike MPP(+) but similar to rotenone, the acetogenin also reduced the survival of non-dopaminergic neurons. Neuronal cell death was not excitotoxic and occurred independently of free radical production. Raising the concentrations of either glucose or mannose in the presence of annonacin restored to a large extent intracellular ATP synthesis and prevented neuronal cell demise. Deoxyglucose reversed the effects of both glucose and mannose. Other hexoses such as galactose and fructose were not protective. Attempts to restore oxidative phosphorylation with lactate or pyruvate failed to provide protection to dopaminergic neurons whereas idoacetate, an inhibitor of glycolysis, inhibited the survival promoting effects of glucose and mannose indicating that these two hexoses acted independently of mitochondria by stimulating glycolysis. In conclusion, our study demonstrates that annonacin promotes dopaminergic neuronal death by impairment of energy production. It also underlines the need to address its possible role in the etiology of some atypical forms of Parkinsonism in Guadeloupe.