Project description:Comparison between the multi-drug resistance Salmonella enteric serotype Newport strains from the US and the pan-susceptible strains from the UK
Project description:Tumor heterogeneity and therapy resistance are hallmarks of pancreatic ductal adenocarcinoma (PDAC). Emerging evidence supports treatment-induced resistance to be a multifactorial process mediated by cellular plasticity involving epigenetic regulation. Here, we used a multi-omics approach to analyze in detail molecular mechanisms underlying MEK inhibitor (MEKi) resistance. Therefore, we characterized different cell stages (parental, MEKi resistant, reverted after different passages of drug withdrawal) in primary cell lines derived from a genetic PDAC mouse model, thereby minimizing inter-individual heterogeneity that could distort genome-wide analyses.
Project description:Phytophthora infestans, the causal agent of late blight disease of potatoes, is mainly controlled by the use of fungicides. Isolates that are resistant to commonly used fungicides have been reported. Also, several studies show that originally mefenoxam-sensitive isolates acquire resistance to this fungicide when exposed to sub-lethal concentrations. This phenomenon, termed ‘mefenoxam-acquired resistance’, has been observed in different Phytophthora species and seems to be unique to mefenoxam. In this study, we aimed to elucidate the molecular mechanism mediating this type of resistance as well as a possible regulatory process behind it. A combination of computational analyses and experimental approaches was used to identify differentially expressed genes with a potential association to the phenomenon. These genes were classified into seven functional groups. Most of them seem to be associated with a pleiotropic drug resistance (PDR) phenotype, typically involved in the expulsion of diverse metabolites, drugs, or other substances out of the cell. Despite the importance of RNApolI for the constitutive resistance of P. infestans to mefenoxam, our results indicate no clear interaction between this protein and the acquisition of mefenoxam resistance. Several small non-coding RNAs (ncRNAs) were found to be differentially expressed and specifically related to genes mediating the PDR phenotype, thus suggesting a possible regulatory process. We propose a model of the molecular mechanisms acting within the cell when P. infestans acquires resistance to mefenoxam after exposed to sub-lethal concentrations of the fungicide. This study provides important insights into P. infestans’ cellular and regulatory functionalities.
Project description:To combat the global burden of malaria, development of new drugs to replace or complement current therapies are urgently required. As drug resistance to existing treatments and clinical failures continue to rise, compounds targeting multiple life cycle stages and species need to be developed as a high priority. Here we show that the compound MMV1557817 is a nanomolar inhibitor of both Plasmodium falciparum and Plasmodium vivax aminopeptidases M1 and M17, leading to inhibition of end stage haemoglobin digestion in asexual parasites. Multi-stage analysis confirmed that MMV1557817 can also kill sexual stage P. falciparum, while cross-resistance studies confirmed the compound targets a mechanism of action distinct to current drug resistance mechanisms. Analysis of cross reactivity to homologous human enzymes shows the compound exhibits a high level of selectivity, whilst safety as well as druggability was confirmed in the murine model P. berghei. MMV1557817-resistant P. falciparum parasites displayed only low-level resistance (<3-fold) and exhibited a slow growth rate that was quickly outcompeted by wild type parasites. MMV1557817-resistant parasites digest significantly more haemoglobin and possess a mutation in PfA-M17 that induces partial destabilization of the PfA-M17 homohexamer, resulting in high-level resistance to specific PfA-M17 inhibition, but enhanced sensitivity to specific PfA-M1 inhibition, and importantly, these parasites were highly sensitive to artemisinin. Overall, these results confirm MMV1557817 as a potential lead compound for further drug development and highlight the potential of dual inhibition of M1 and M17 as an effective multi-species drug targeting strategy.