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A novel inhibitor of P. aeruginosa folate metabolism exploits metabolic differences for narrow-spectrum antibiotic targeting

ABSTRACT: A novel inhibitor of P. aeruginosa folate metabolism exploits metabolic differences for narrow-spectrum antibiotic targeting

PROVIDER: PRJNA1051048 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27173995_1.fastq.gz	Fastqsanger.gz
	SRR27173995_2.fastq.gz	Fastqsanger.gz
	SRR27173996_1.fastq.gz	Fastqsanger.gz
	SRR27173996_2.fastq.gz	Fastqsanger.gz
	SRR27173997_1.fastq.gz	Fastqsanger.gz

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Data files for "A novel inhibitor of P. aeruginosa folate metabolism exploits metabolic differences for narrow-spectrum antibiotic targeting"

Project description:Raw MS files for the manuscript, "A novel inhibitor of P. aeruginosa folate metabolism exploits metabolic differences for narrow-spectrum antibiotic targeting", by Chain et al.

2023-12-07 | MSV000093598 | MassIVE

A novel inhibitor of P. aeruginosa folate metabolism exploits metabolic differences for narrow-spectrum antibiotic targeting

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

Deep learning-guided discovery of a narrow-spectrum antibiotic against Acinetobacter baumannii

Project description:Acinetobacter baumannii is a nosocomial Gram-negative pathogen that often displays multidrug-resistance due to its robust outer membrane and its ability to acquire and retain extracellular DNA. Moreover, it can survive for prolonged durations on surfaces and is resistant to desiccation. Discovering new antibiotics against A. baumannii has proven challenging through conventional screening approaches. Fortunately, machine learning methods allow for the rapid exploration of chemical space, increasing the probability of discovering new chemical matter with antibacterial activity against this burdensome pathogen. Here, we screened ~7,500 molecules for those that inhibited the growth of A. baumannii in vitro. We trained a deep neural network with this growth inhibition dataset and performed predictions on the Drug Repurposing Hub for structurally novel molecules with activity against A. baumannii. Through this approach, we discovered abaucin, an antibacterial compound with narrow-spectrum activity against A. baumannii, which could overcome intrinsic and acquired resistance mechanisms in clinical isolates. Further investigations revealed that abaucin perturbs lipoprotein trafficking through a mechanism involving LolE, a functionally conserved protein that contributes to shuttling lipoproteins from the inner membrane to the outer membrane. Moreover, abaucin was able to control an A. baumannii infection in a murine wound model. Together, this work highlights the utility of machine learning in discovering new antibiotics and describes a promising lead with narrow-spectrum activity against a challenging Gram-negative pathogen.

2023-02-01 | GSE214305 | GEO

GNPS - Data files for metabolomics

2023-12-07 | MSV000093598 | GNPS

Deep learning-guided discovery of a narrow-spectrum antibiotic against Acinetobacter baumannii

Project description:Deep learning-guided discovery of a narrow-spectrum antibiotic against Acinetobacter baumannii

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Narrow- and Broad-Spectrum Antibiotic Use among U.S. Children.

Project description:ObjectivesTo provide updated estimates of narrow- and broad-spectrum antibiotic use among U.S. children.Data sourcesLinked nationally representative data from the 2004-2010 Medical Expenditure Panel Survey Household Component and the 2000 Decennial Census.Study designRelationships between individual-, family-, and community-level characteristics and the use of antibiotics overall and in the treatment of respiratory tract infections (RTIs) are examined using multinomial choice models.Principal findingsMore than one quarter (27.3 percent) of children used at least one antibiotic each year with 12.8 percent using broad-spectrum and 18.5 percent using narrow-spectrum antibiotics. Among children with use, more than two-thirds (68.6 percent) used antibiotics to treat RTIs. Multivariate models revealed many differences across groups in antibiotic use, overall and in the treatment of RTIs. Differential use was associated with a broad range of factors related to need (e.g., age, health status), resources (e.g., insurance status, parental income, and education), race-ethnicity, and Census region.ConclusionsDespite encouraging reports regarding the declining use of antibiotics, large differences in use associated with resources, race-ethnicity, and Census regions suggest a need for further improvement in the judicious and appropriate prescribing of antibiotics for U.S. children.

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2024-02-09 | GSE245438 | GEO

Dietary folate depletion and repletion

Project description:This SuperSeries is composed of the following subset Series: GSE9242: Dietary folate depletion and repletion in A/J and C57BL/6J mice GSE9243: Dietary folate depletion and repletion in C57BL/6J mice, ApoE knockout mice, and choline supplemented C57BL/6J mice Keywords: SuperSeries Refer to individual Series

2010-06-20 | E-GEOD-9245 | biostudies-arrayexpress

Gene expression alteration in human fibroblast cells after folate depletion

Project description:The molecular basis linking folate deficiency to certain health conditions and developmental defects is complex and not fully understood. In this study, we examined the consequences of folate deficiency on global gene expression by microarray analysis and compared transcript levels in normal human fibroblast cells (GM03349) grown in folate deficient and sufficient medium. Keywords: folate depletion, stress response, comparative genomic hybridization

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