Phenotypic convergent evolution towards fosfomycin collateral sensitivity of Pseudomonas aeruginosa antibiotic resistant mutants
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA641152 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12070818_1.fastq.gz | Fastqsanger.gz | |||
| SRR12070818_2.fastq.gz | Fastqsanger.gz | |||
| SRR12070819_1.fastq.gz | Fastqsanger.gz | |||
| SRR12070819_2.fastq.gz | Fastqsanger.gz | |||
| SRR12070820_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 10 |
Similar Datasets
Project description:In this work we describe a robust fosfomycin collateral sensitivity phenotype of Pseudomonas aeruginosa resistant mutants selected by antibiotics from different structural families. The underlying mechanism was the reduced expression of the genes encoding the peptidoglycan-recycling pathway, which preserves the peptidoglycan synthesis in situations where the de novo synthesis is blocked, and of fosA, encoding a fosfomycin-inactivating enzyme.
2022-03-02 | GSE153006 | GEO
Project description:Cationic antimicrobial peptides (CAPs) are promising novel alternatives to conventional antibacterial agents, but the overlap in resistance mechanisms between small-molecule antibiotics and CAPs is unknown. Does evolution of antibiotic resistance decrease (cross-resistance) or increase (collateral sensitivity) susceptibility to CAPs? We systematically addressed this issue by studying the susceptibilities of a comprehensive set of antibiotic resistant Escherichia coli strains towards 24 antimicrobial peptides. Strikingly, antibiotic resistant bacteria frequently showed collateral sensitivity to CAPs, while cross-resistance was relatively rare. We identified clinically relevant multidrug resistance mutations that simultaneously elevate susceptibility to certain CAPs. Transcriptome and chemogenomic analysis revealed that such mutations frequently alter the lipopolysaccharide composition of the outer cell membrane and thereby increase the killing efficiency of membrane-interacting antimicrobial peptides. Furthermore, we identified CAP-antibiotic combinations that rescue the activity of existing antibiotics and slow down the evolution of resistance to antibiotics. Our work provides a proof of principle for the development of peptide based antibiotic adjuvants that enhance antibiotic action and block evolution of resistance.
2018-03-29 | GSE96706 | GEO
Project description:Phenotypic convergence in response to drug exposure supports exploitation of collateral sensitivity to counter drug resistance
| PRJEB22929 | ENA
Project description:Collateral sensitivity (CS) is a promising alternative approach to counteract the rising problem of antibiotic resistance (ABR). CS occurs when the acquisition of resistance to one antibiotic produces increased susceptibility to a second antibiotic. Recent studies have focused on CS strategies designed against ABR mediated by chromosomal mutations. However, one of the main drivers of ABR in clinically relevant bacteria is the horizontal transfer of ABR genes mediated by plasmids. Here, we report the first analysis of CS associated with the acquisition of complete ABR plasmids, including the clinically important carbapenem-resistance conjugative plasmid pOXA-48. In addition, we describe the conservation of CS in clinical E. coli isolates and its application to selectively kill plasmid-carrying bacteria. Our results provide new insights that establish the basis for developing CS-informed treatment strategies to combat plasmid-mediated ABR.
| S-EPMC7837676 | biostudies-literature
Project description:Antibiotic collateral sensitivity (CS) occurs when a bacterium that acquires resistance to a treatment drug exhibits decreased resistance to a different drug. Here we identify reciprocal CS networks and candidate genes in Burkholderia multivorans. Burkholderia multivorans was evolved to become resistant to each of six antibiotics. The antibiogram of the evolved strain was compared with the immediate parental strain to determine CS and cross-resistance. The evolution process was continued for each resistant strain. CS interactions were observed in 170 of 279 evolved strains. CS patterns grouped into two clusters based on the treatment drug being a β-lactam antibiotic or not. Reciprocal pairs of CS antibiotics arose in ≥25% of all evolved strains. A total of 68 evolved strains were subjected to whole-genome sequencing and the resulting mutation patterns were correlated with antibiograms. Analysis revealed there was no single gene responsible for CS and that CS seen in B. multivorans is likely due to a combination of specific and non-specific mutations. The frequency of reciprocal CS, and the degree to which resistance changed, suggests a long-term treatment strategy; when resistance to one drug occurs, switch to use of the other member of the reciprocal pair. This switching could theoretically be continued indefinitely, allowing life-long treatment of chronic infections with just two antibiotics.
| S-EPMC8759574 | biostudies-literature
Project description:Determining the mechanisms of action of drug molecules that modulate circadian rhythms is critical to develop novel compounds to treat clock disorders. Here we employed Phenotypic Proteomic Profiling (PPP) integrating multipronged proteomics approaches including global proteome, phosphoproteome, kinome mapping, and proteome-wide profiling of thermal stability (TPP) to systematically determine convergent molecular targets of four circadian period lengthening compounds (Longdaysin, Roscovitine, Purvalanol A, and SP600125) in human cells. We demonstrate convergent changes in phosphorylation level and activity of several proteins and kinases involved in vital signaling pathways including MAPK, NGF, BCR, AMPK, and mTOR signaling by the compounds. Kinome profiling using desthiobiotin-ATP enrichment quantitative proteomics and radiometric assays further indicated inhibition of CKId, ERK1/2, CDK2/7, TNIK and STK26 activity as a common mechanism of action for the compounds. Pharmacological or genetic inhibition of several convergent kinases resulted in circadian period lengthening, establishing them as novel bone fide circadian targets. TPP analysis using live cells revealed binding of these drugs to clock regulatory kinases, signaling molecules, and ubiquitination mediator (F-box) proteins. Phenotypic proteomic profiling thus establishes a set of novel circadian clock effectors.
2019-11-25 | PXD014186 | Pride
Project description:Burkholderia multivorans is a member of the Burkholderia cepacia complex whose members are inherently resistant to many antibiotics and can cause chronic lung infections in patients with cystic fibrosis. A possible treatment for chronic infections arises from the existence of collateral sensitivity (CS)-acquired resistance to a treatment antibiotic results in a decreased resistance to a nontreatment antibiotic. Determining CS patterns for bacteria involved in chronic infections may lead to sustainable treatment regimens that reduce development of multidrug-resistant bacterial strains. CS has been found to occur in Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. Here, we report that B. multivorans exhibits antibiotic CS, as well as cross-resistance (CR), describe CS and CR networks for six antibiotics (ceftazidime, chloramphenicol, levofloxacin, meropenem, minocycline, and trimethoprim-sulfamethoxazole), and identify candidate genes involved in CS. Characterization of CS and CR patterns allows antibiotics to be separated into two clusters based on the treatment drug to which the evolved strain developed primary resistance, suggesting an antibiotic therapy strategy of switching between members of these two clusters.
| S-EPMC6978779 | biostudies-literature
Project description:Antibiotic resistance increasingly limits the success of antibiotic treatments, and physicians require new ways to achieve efficient treatment despite resistance. Resistance mechanisms against a specific antibiotic class frequently confer increased susceptibility to other antibiotic classes, a phenomenon designated collateral sensitivity (CS). An informed switch of antibiotic may thus enable the efficient treatment of resistant strains. CS occurs in many pathogens, but the mechanisms that generate hypersusceptibility are largely unknown. We identified several molecular mechanisms of CS against the antibiotic nitrofurantoin (NIT). Mutants that are resistant against tigecycline (tetracycline), mecillinam (β-lactam), and protamine (antimicrobial peptide) all show CS against NIT. Their hypersusceptibility is explained by the overexpression of nitroreductase enzymes combined with increased drug uptake rates, or increased drug toxicity. Increased toxicity occurs through interference of the native drug-response system for NIT, the SOS response, with growth. A mechanistic understanding of CS will help to develop drug switches that combat resistance.
| S-EPMC7004380 | biostudies-literature
Project description:The intrinsic collateral cleavage activity of Cas13d,which refers to the gRNA-independent degradation of bystander RNA, significantly limits its therapeutic potential. To extensively evaluate the collateral effects of hpCas13d genome-wide, we conducted RNA-seq analysis of the transcriptome in HEK293T cells after the transfections with dCas13d, wtCas13d, hpCas13d, and hfCas13d . Compared to dCas13d, wtCas13d with a PPIA gRNA (reported to induce the significant collateral cleavage) resulted in significant downregulations of thousands genes. In sharp contrast, hpCas13d and hfCas13d showed much less off-target genes, respectively. These findings demonstrate that hpCas13d exhibits reduced collateral activity, rendering it suitable for in vivo applications.
2024-02-28 | GSE260500 | GEO