Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1010194 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25814368_1.fastq.gz | Fastqsanger.gz | |||
| SRR25814368_2.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 2 of 2 |
Similar Datasets
Project description:There is a need to discover and develop non-toxic antibiotics that are effective against metabolically dormant bacteria, which underlie chronic infections and promote antibiotic resistance. Traditional antibiotic discovery has historically favored compounds effective against actively metabolizing cells, a property that is not predictive of efficacy in metabolically inactive contexts. Here, we combine a stationary-phase screening method with deep learning-powered virtual screens and toxicity filtering to discover compounds with lethality against metabolically dormant bacteria and favorable toxicity profiles. The most potent and structurally novel compound without any obvious mechanistic liability was semapimod, an anti-inflammatory drug effective against stationary-phase E. coli and A. baumannii. Integrating microbiological assays, biochemical measurements, and single-cell microscopy, we show that semapimod selectively disrupts and permeabilizes the bacterial outer membrane by binding lipopolysaccharide. This work illustrates the value of harnessing non-traditional screening methods and deep learning models to identify non-toxic antibacterial compounds that are effective in infection-relevant contexts.
2023-08-21 | PXD044230 | Pride
Project description:Inosine 5’-monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo guanine biosynthesis and is conserved from humans to bacteria, where it is called GuaB. We developed a series of potent inhibitors that selectively target GuaB over its human homolog. Here we show that these GuaB inhibitors are bactericidal, generate phenotypic signatures that are distinct from other antibiotics, and elicit different time-kill kinetics and regulatory responses in two important gram-negative pathogens: Acinetobacter baumannii and Escherichia coli. Specifically, the GuaB inhibitor G6 rapidly kills A. baumannii but only kills E. coli after 24 hours. After exposure to G6, the expression of genes involved in purine biosynthesis and stress responses change in opposite directions while siderophore biosynthesis is downregulated in both species. Our results suggest that different species respond to GuaB inhibition using distinct regulatory programs, and possibly explain the different bactericidal kinetics upon GuaB inhibition. The comparison highlights opportunities for developing GuaB inhibitors as novel antibiotics.
2024-08-25 | GSE275261 | GEO
Project description:The general assumption is that when bacteria run out of nutrients they become dormant or form spores. Here we show, using a new technique, that under deep starvation conditions non-sporulating Bacillus subtilis cells do not become dormant but continue to grow. B. subtilis can form (endo)spores and this has been regarded as the principal mechanism through which it survives long periods of nutrient depletion. However, in this study we demonstrate that non-sporulating B. subtilis cells can survive deep starvation conditions for many months. During this period, cells adopt an almost coccoid shape and become tolerant to antibiotics and oxidative stress. Interestingly, these cells appeared to be metabolically active, and transcriptome analyses indicated that their gene-expression profile differs substantially from both stationary phase cells, and exponentially growing cells. Surprisingly, using an inhibitor for cell division, we discovered that these coccoid-like B. subtilis cells are not dormant but actually grow and divide, albeit with a doubling time of ~4 days. It emerged that secreted proteases, allowing acquisition of nutrients from lysed brethren, are essential for this growth mode. In fact, nutrient levels comparable to 10,000 times diluted LB (Lysogeny broth) appeared to be sufficient to sustain this growth. The very slow growth provides an alternative strategy for B. subtilis to survive nutrient depletion and environmental stresses. We propose to call this the oligotrophic growth state. This state might be common among bacterial species to survive deep starvation conditions.
2018-08-01 | GSE102140 | GEO
Project description:Persisters represent a small bacterial population that is dormant and that survives under antibiotic treatment without experiencing genetic adaptation. Persisters are also considered one of the major reasons for recalcitrant chronic bacterial infections. Although several mechanisms of persister formation have been proposed, it is not clear how cells enter the dormant state in the presence of antibiotics or how persister cell formation can be effectively controlled. A fatty acid compound, cis-2-decenoic acid, was reported to decrease persister formation as well as revert the dormant cells to a metabolically active state. We reasoned that some fatty acid compounds may be effective in controlling bacterial persistence because they are known to benefit host immune systems. This study investigated persister cell formation by pathogens that were exposed to nine fatty acid compounds during antibiotic treatment. We found that three medium chain unsaturated fatty acid ethyl esters (ethyl trans-2-decenoate, ethyl trans-2-octenoate, and ethyl cis-4-decenoate) decreased the level of Escherichia coli persister formation up to 110-fold when cells were exposed to ciprofloxacin or ampicillin antibiotics. RNA sequencing analysis and gene deletion persister studies elucidated that these fatty acids inhibit bacterial persistence by regulating antitoxin HipB. A similar persister cell reduction was observed for pathogenic E. coli EDL933, Pseudomonas aeruginosa PAO1, and Serratia marcescens ICU2-4 strains. This study demonstrates that fatty acid ethyl esters can be used to disrupt bacterial dormancy to combat persistent infectious diseases.
2018-08-08 | GSE112545 | GEO
Project description:Pseudomonas aeruginosa is a leading cause of hospital acquired infections for which the development of new antibiotics is urgently needed. Unlike most enteric bacteria, P. aeruginosa lacks thymidine kinase and thymidine phosphorylase activity, and thus cannot scavenge exogenous thymine. An appealing strategy to selectively target P. aeruginosa while leaving the healthy microbiome largely intact would thus be to disrupt thymidine synthesis while providing exogenous thymine. However, this approach was previously intractable because known antibiotics that perturb thymidine synthesis are largely inactive against P. aeruginosa. Here, we characterize a novel dihydrofolate reductase inhibitor, fluorofolin, that exhibits significant activity against P. aeruginosa in culture and in a mouse thigh infection model. Fluorofolin is active against a wide range of clinical P. aeruginosa isolates resistant to known antibiotics, including critical antibiotic development priorities expressing the beta-lactamases KPC-5 and NDM-1. Importantly, in the presence of thymine supplementation, fluorofolin activity is selective for P. aeruginosa. Resistance to fluorofolin can emerge through overexpression of the efflux pumps MexCD-OprJ and MexEF-OprN. However, these mutants also decrease pathogenesis, in part due to increased export of quorum sensing precursors leading to decreased virulence factor production. Our findings thus demonstrate how understanding species-specific genetic differences and discovery of an antibiotic with a widely conserved target can enable selective targeting of important pathogens while revealing new tradeoffs between resistance and pathogenesis.
2024-02-07 | GSE249862 | GEO
Project description:Antimicrobial resistance is a leading mortality factor worldwide. Here we report the discovery of clovibactin, a new antibiotic, isolated from uncultured soil bacteria. Clovibactin efficiently kills drug-resistant Gram-positivebacterial pathogens without detectable resistance. Using biochemical assays,solid-state NMR, and atomic force microscopy, we dissect its mode of action. Clovibactin blocks cell wall synthesis by targeting pyrophosphate of multiple essential peptidoglycan precursors (C55PP, Lipid II, LipidWTA). Clovibactin uses anunusual hydrophobic interface to tightly wrap aroundpyrophosphate, butbypasses the variable structural elements of precursors, accounting for the lack of resistance. Selective and efficient target binding is achieved by the sequestration of precursors into supramolecular fibrils that only form on bacterial membranes that contain lipid-anchored pyrophosphate groups.Uncultured bacteria offer a rich reservoir of antibiotics with new mechanisms of action that could replenish the antimicrobial discovery pipeline.
2023-08-22 | GSE228489 | GEO
Project description:Mycobacterium abscessus is an opportunistic pathogen notorious for its resistance to most classes of antibiotics and low cure rates. In addition to the highly impermeable mycomembrane, M. abscessus carries an array of shared and species-specific defence mechanisms. However, it remains unknown whether M. abscessus’ antibiotic stress response is fine-tuned or an all-or-nothing response. A deeper understanding of underlying resistance and tolerance mechanisms is pivotal in development of targeted therapeutic regimens. We elucidate the transcriptomic response of M. abscessus to antibiotics recommended in treatment guidelines. The M. abscessus ATCC 19977 strain was used. Bacteria were subjected to sub-inhibitory concentrations of drugs for 4- and 24-hours, followed by RNA sequencing. In addition, time-kill kinetic analysis was performed using bacteria after pre-exposure to clarithromycin, amikacin or tigecycline for 24-hours. Lastly, Pan-genome analysis of 35 strains from all three subspecies was performed. Mycobacterium abscessus shows both drug-specific and communal transcriptomic responses to antibiotic exposure. Key features of its tolerance to antibiotics are drug-specific converting enzymes, target protection and shifts in its respiratory chain and metabolic state. The observed transcriptomic responses are likely not strain-specific, as genes involved in tolerance are found in all included strains, with the exception of erm(41) in M. abscessus subspecies massiliense. Due to the communal response elicited by ribosomal-targeting antibiotics, exposure to any of these drugs rapidly induces tolerance mechanisms that decrease susceptibility to ribosome-targeting drugs from multiple classes. Screening high-risk patients (e.g. those with bronchiectasis) for M. abscessus infection prior to starting macrolide or aminoglycoside maintenance therapy is warranted.
2022-01-25 | GSE163621 | GEO
Project description:The initiation of DNA synthesis in metazoans is restricted to a group of baseline replication origins, whereas other (dormant) origins do not initiate replication despite recruiting apparently indistinguishable pre-replication complexes. Dormant origins are activated as backups when DNA synthesis stalls. We report that dormant origins selectively bind CDK-phosphorylated RecQL4 (pRecQL4), a helicase mutated in Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. In unperturbed cells, pRecQL4 restricts replication initiation to baseline origins by preventing dormant origins from binding the essential initiation factor MTBP. When cells encounter replication stress, pRecQL4 first promotes the dissociation of MTBP from chromatin, and then enables its redistribution to both baseline and dormant origins, facilitating compensatory initiation to complete genome duplication. Thus, MTBP-pRecQL4 interactions modulate replication origin choice and facilitate recovery from replication stress.
2025-04-06 | GSE276856 | GEO
Project description:EGFR inhibitors selectively kill CD34+ leukemia cells and induced clinical remission in patients with high percentage of CD34+ blast
2020-12-30 | PXD023328 |
Project description:The bacterial cell wall has been a celebrated target for antibiotics and holds real promise as a target for the discovery of new chemical matter to surmount pervasive multi-drug resistance among pathogenic bacteria. While the walls of Gram-negative bacteria are composed primarily of peptidoglycan, those of Gram-positives are more substantial and contain, in addition, large amounts of the polymer teichoic acid, covalently attached to peptidoglycan. Wall teichoic acids are a diverse group of phosphate-rich, extracellular polysaccharides that have been largely regarded as ancillary cell surface components. Recently, wall teichoic acid was shown to be essential to the proper rod-shaped cell morphology of the prototype Gram-positive bacterium Bacillus subtilis and an important virulence factor for the human pathogen Staphylococcus aureus. Thus wall teichoic acid synthesis is an intriguing target for the development of new cell wall-active antibiotics. Nevertheless, recent studies have shown that the dispensability of genes encoding teichoic acid biosynthetic enzymes in both B. subtilis and S. aureus is paradoxical and complex. Here, we report here on the discovery of a promoter (PywaC), which is sensitive to lesions in teichoic acid synthesis. Using this promoter we developed a luminescent, cell-based, reporter system to take a chemical-genetic approach to understanding the complexity of wall teichoic acid biogenesis using a large collection of antibiotics of well characterized biological activity. Our results reveal surprising interactions among undecaprenol, peptidoglycan and teichoic acid biosynthesis that help explain the complexity of teichoic acid gene dispensability. Furthermore, the new reporter assay represents an exciting avenue for the discovery of novel antibacterial molecules that impinge broadly on Gram-positive bacterial cell wall biogenesis. Keywords: comparison between depleted and repleted tagD mutant
2008-03-01 | GSE7373 | GEO