ArticlePLoS computational biology2019
Systems-level analysis of NalD mutation, a recurrent driver of rapid drug resistance in acute Pseudomonas aeruginosa infection.
Article in PLoS computational biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 18 citations in OpenAlex.
- Mechanisms involved in cefiderocol resistance in FrenchAntimicrobial agents and chemotherapy · 2026Article
- Beyond Resistance Genes:Life (Basel, Switzerland) · 2026Review
- Metabiosis underlies a microbiota permissive to Pseudomonadota and increases the risk of gut-borne bloodstream infection.bioRxiv : the preprint server for biology · 2026Article
- Emergence of outbreak-driving high-riskMicrobial genomics · 2026Article
- Genomic and Transcriptomic Profiling of a Highly VirulentMicroorganisms · 2025Article
- Ecological management of the microbiota in patients with cancer.Nature reviews. Clinical oncology · 2025Review
- Recent insights into actinobacteria research in antimicrobial resistance: a review.Molecular biology reports · 2025Review
- Keeping up with the pathogens: improved antimicrobial resistance detection and prediction from Pseudomonas aeruginosa genomes.Genome medicine · 2024Article
- Antibiotic influx and efflux in Pseudomonas aeruginosa: Regulation and therapeutic implications.Microbial biotechnology · 2024Review
- Comparative molecular profiling of multidrug-resistantJAC-antimicrobial resistance · 2024Article
- Role of face masks and ventilation rates in mitigating respiratory disease transmission in ICU.Scientific reports · 2023Article
- Whole-Genome Sequencing Reveals Diversity of Carbapenem-ResistantAntimicrobial agents and chemotherapy · 2022Article
- Genomic characterization of denitrifying methylotrophic Pseudomonas aeruginosa strain AAK/M5 isolated from municipal solid waste landfill soil.World journal of microbiology & biotechnology · 2022Article
- Genome-scale metabolic modeling in antimicrobial pharmacology.Engineering microbiology · 2022Review
- Antibiotic Resistance in Pseudomonas.Advances in experimental medicine and biology · 2022Article
- Coming from the Wild: Multidrug Resistant Opportunistic Pathogens Presenting a Primary, Not Human-Linked, Environmental Habitat.International journal of molecular sciences · 2021Review
- Article
- Compilation of longitudinal microbiota data and hospitalome from hematopoietic cell transplantation patients.Scientific data · 2021Article
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Authors and funding
10 authors at 5 institutions in 1 country.
Funding
Abstract
Pseudomonas aeruginosa, a main cause of human infection, can gain resistance to the antibiotic aztreonam through a mutation in NalD, a transcriptional repressor of cellular efflux. Here we combine computational analysis of clinical isolates, transcriptomics, metabolic modeling and experimental validation to find a strong association between NalD mutations and resistance to aztreonam-as well as resistance to other antibiotics-across P. aeruginosa isolated from different patients. A detailed analysis of one patient's timeline shows how this mutation can emerge in vivo and drive rapid evolution of resistance while the patient received cancer treatment, a bone marrow transplantation, and antibiotics up to the point of causing the patient's death. Transcriptomics analysis confirmed the primary mechanism of NalD action-a loss-of-function mutation that caused constitutive overexpression of the MexAB-OprM efflux system-which lead to aztreonam resistance but, surprisingly, had no fitness cost in the absence of the antibiotic. We constrained a genome-scale metabolic model using the transcriptomics data to investigate changes beyond the primary mechanism of resistance, including adaptations in major metabolic pathways and membrane transport concurrent with aztreonam resistance, which may explain the lack of a fitness cost. We propose that metabolic adaptations may allow resistance mutations to endure in the absence of antibiotics and could be targeted by future therapies against antibiotic resistant pathogens.
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