Autism spectrum disorders (ASDs) are epidemically explosive clinical entities, but their pathogenesis is still unclear and a definitive cure does not yet exist. Rett syndrome (RTT) is a rare genetically determined cau...Autism spectrum disorders (ASDs) are epidemically explosive clinical entities, but their pathogenesis is still unclear and a definitive cure does not yet exist. Rett syndrome (RTT) is a rare genetically determined cause of autism linked to mutations in the X-linked MeCP2 gene or, more rarely, in CDKL5 or FOXG1. A wide phenotypical heterogeneity is a known feature of the disease. Although several studies have focused on the molecular genetics and possible protein changes at different levels, to date very little attention has been paid to fatty acids in this disease, which could be considered as a natural paradigm for the ASDs. To this regard, a quite enigmatic feature of the disease is the evidence in the affected patients of an extensive peroxidation of polyunsaturated fatty acids (arachidonic acid, AA, docosaexahenoic acid, DHA, adrenic acid, AdA and, to a lesser extent, eicosapentaenoic acid, EPA), in contrast with amelioration of the redox changes and phenotypical severity following the supplementation of some of those same fatty acids (DHA + EPA). Therefore, fatty acids may represent a kind of Janus Bifrons in the particular context of RTT. Here, we propose a rational explanation for this apparent “fatty acid paradox” in RTT. A better understanding of this paradox could also be of help to get a better insight into the complex mechanism of action for polyunsaturated fatty acids in health and disease.展开更多
Gram‐negative bacteria are particularly prone to developing antimicrobial resistance(AMR),as evidenced by the WHO's ESKAPEE list of high‐priority pathogens.One strategy that has increased is the use of antibioti...Gram‐negative bacteria are particularly prone to developing antimicrobial resistance(AMR),as evidenced by the WHO's ESKAPEE list of high‐priority pathogens.One strategy that has increased is the use of antibiotic enhancers,which can reempower abandoned or poorly active antibiotics against the resistant strain of interest.In this study,the polyamino‐isoprenyl antibiotic enhancer,NV716,was tested in combination with two families of multi‐target Ser/Cys‐based enzyme inhibitors,the oxadiazolone derivatives(OX)and the Cyclipostins and Cyclophostin analogs(CyC),which are inactive against Gram‐negative ESKAPEE bacteria,to potentiate their antibacterial activity and thus make them active against these bacteria.We demonstrated that NV716 potentiates some OX and CyC compounds by permeabilizing the outer membrane and thus by increasing the inhibitor accumulation,as shown by fluorescence microscopy.By using the click‐chemistry activity‐based protein profiling(ABPP)approach coupled with proteomic analysis,we also confirmed the multi‐target nature of the best OX and CyC inhibitors by identifying their target proteins on a bacterial culture of Enterobacter cloacae.Remarkably,a large set of these identified proteins had already been captured in previous ABPP experiments conducted on Mycobacterium tuberculosis and/or Mycobacterium abscessus culture.Furthermore,we showed that five of the identified target proteins were present in a total lysate of Pseudomonas aeruginosa.Importantly,these latter enzymes are highly conserved among Gram‐negative bacteria,with two of them annotated as essential for bacterial survival.These results provide proof of concept that both OX and CyC,if successfully potentiated,could be used against ESKAPEE Gram‐negative bacteria.展开更多
文摘Autism spectrum disorders (ASDs) are epidemically explosive clinical entities, but their pathogenesis is still unclear and a definitive cure does not yet exist. Rett syndrome (RTT) is a rare genetically determined cause of autism linked to mutations in the X-linked MeCP2 gene or, more rarely, in CDKL5 or FOXG1. A wide phenotypical heterogeneity is a known feature of the disease. Although several studies have focused on the molecular genetics and possible protein changes at different levels, to date very little attention has been paid to fatty acids in this disease, which could be considered as a natural paradigm for the ASDs. To this regard, a quite enigmatic feature of the disease is the evidence in the affected patients of an extensive peroxidation of polyunsaturated fatty acids (arachidonic acid, AA, docosaexahenoic acid, DHA, adrenic acid, AdA and, to a lesser extent, eicosapentaenoic acid, EPA), in contrast with amelioration of the redox changes and phenotypical severity following the supplementation of some of those same fatty acids (DHA + EPA). Therefore, fatty acids may represent a kind of Janus Bifrons in the particular context of RTT. Here, we propose a rational explanation for this apparent “fatty acid paradox” in RTT. A better understanding of this paradox could also be of help to get a better insight into the complex mechanism of action for polyunsaturated fatty acids in health and disease.
基金supported by the CNRS,INSERM,and Aix Marseille University.Proteomics analyses were carried out using the mass spectrometry facility of Marseille Proteomics(marseille‐proteomique.univ‐amu.fr)supported by IBISAthe Cancéropôle PACA,the Provence‐Alpes‐Côte d'Azur Region,the Institut Paoli‐Calmettes,and Fonds Européen de Développement Regional(FEDER)+1 种基金Emma Forest PhD fellowship is supported by the Ministère de l'Enseignement Supérieur et de la RechercheThe authors would like to thank Pierre Santucci(LISM UMR7255 CNRS)for his help with Biorender.
文摘Gram‐negative bacteria are particularly prone to developing antimicrobial resistance(AMR),as evidenced by the WHO's ESKAPEE list of high‐priority pathogens.One strategy that has increased is the use of antibiotic enhancers,which can reempower abandoned or poorly active antibiotics against the resistant strain of interest.In this study,the polyamino‐isoprenyl antibiotic enhancer,NV716,was tested in combination with two families of multi‐target Ser/Cys‐based enzyme inhibitors,the oxadiazolone derivatives(OX)and the Cyclipostins and Cyclophostin analogs(CyC),which are inactive against Gram‐negative ESKAPEE bacteria,to potentiate their antibacterial activity and thus make them active against these bacteria.We demonstrated that NV716 potentiates some OX and CyC compounds by permeabilizing the outer membrane and thus by increasing the inhibitor accumulation,as shown by fluorescence microscopy.By using the click‐chemistry activity‐based protein profiling(ABPP)approach coupled with proteomic analysis,we also confirmed the multi‐target nature of the best OX and CyC inhibitors by identifying their target proteins on a bacterial culture of Enterobacter cloacae.Remarkably,a large set of these identified proteins had already been captured in previous ABPP experiments conducted on Mycobacterium tuberculosis and/or Mycobacterium abscessus culture.Furthermore,we showed that five of the identified target proteins were present in a total lysate of Pseudomonas aeruginosa.Importantly,these latter enzymes are highly conserved among Gram‐negative bacteria,with two of them annotated as essential for bacterial survival.These results provide proof of concept that both OX and CyC,if successfully potentiated,could be used against ESKAPEE Gram‐negative bacteria.
