ArticleAntimicrobial agents and chemotherapy2015
Pharmacodynamic Profiling of a Siderophore-Conjugated Monocarbam in Pseudomonas aeruginosa: Assessing the Risk for Resistance and Attenuated Efficacy.
Article in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 76 citations in OpenAlex.
- Mechanisms of Reduced Susceptibility to Cefiderocol Among Isolates from the CREDIBLE-CR and APEKS-NP Clinical Trials.Microbial drug resistance (Larchmont, N.Y.) · 2022Trial
- Understanding mechanisms of reduced cefiderocol susceptibility in pvdS and fecI mutants of Pseudomonas aeruginosa.The Journal of antimicrobial chemotherapy · 2026Article
- Siderophore cephalosporins.EcoSal Plus · 2025Review
- The Therapeutic Potential of Cefiderocol in the Treatment of Multidrug-Resistant Gram-Negative Bacteria: A Narrative Review.Journal of clinical medicine · 2025Review
- Novel PiuC, PirA, and PiuA mutations leading toMicrobiology spectrum · 2025Article
- Bacterial siderophores: diversity, uptake pathways and applications.Nature reviews. Microbiology · 2025Review
- High-Throughput Discovery of Synthetic Siderophores for Trojan Horse Antibiotics.ACS infectious diseases · 2024Article
- In vitro resistance development gives insights into molecular resistance mechanisms against cefiderocol.The Journal of antibiotics · 2024Article
- Successful Treatment of Carbapenem-Resistant Acinetobacter baumannii Meningitis With Sulbactam-Durlobactam.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2024Article
- Conjugation to Native and Nonnative Triscatecholate Siderophores Enhances Delivery and Antibacterial Activity of a β-Lactam to Gram-Negative Bacterial Pathogens.Journal of the American Chemical Society · 2024Article
- Siderophores promote cooperative interspecies and intraspecies cross-protection against antibiotics in vitro.Nature microbiology · 2024Article
- Specificity and mechanism of TonB-dependent ferric catecholate uptake by Fiu.Frontiers in microbiology · 2024Article
- Synthesis and Characterization of DOTAM-Based Sideromycins for Bacterial Imaging and Antimicrobial Therapy.ACS infectious diseases · 2023Article
- Iron Acquisition Mechanisms and Their Role in the Virulence of Acinetobacter baumannii.Infection and immunity · 2022Review
- Harnessing microbial iron chelators to develop innovative therapeutic agents.Journal of advanced research · 2022Review
- Assessment of sustained efficacy and resistance emergence under human-simulated exposure of cefiderocol againstJAC-antimicrobial resistance · 2022Article
- In a Pinch: Cefiderocol for CRAB Infections.Antimicrobial agents and chemotherapy · 2022Article
- Cefiderocol- Compared to Colistin-Based Regimens for the Treatment of Severe Infections Caused by Carbapenem-Resistant Acinetobacter baumannii.Antimicrobial agents and chemotherapy · 2022Observational
- Understanding the Potential and Risk of Bacterial Siderophores in Cancer.Frontiers in oncology · 2022Review
- New Perspectives on Antimicrobial Agents: Cefiderocol.Antimicrobial agents and chemotherapy · 2021Review
Corrections and comments
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Authors and funding
17 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosa by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC (fT>MIC). To closer emulate the conditions of the in vivo model, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake: piuA, piuC, pirR, fecI, and pvdS. Against four P. aeruginosa isolates, SMC-3176 displayed predictable efficacy corresponding to the fT>MIC using the MIC in CDMHB (R(2) = 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate for P. aeruginosa isolate JJ 4-36, as the in vivo responses were inconsistent with fT>MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against which in vivo failures of another siderophore-conjugated β-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy in P. aeruginosa due to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantial in vivo testing is warranted for compounds using the siderophore approach to thoroughly screen for this in vitro-in vivo disconnect in P. aeruginosa.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.