Adaptation-Based Resistance to Siderophore-Conjugated Antibacterial Agents by Pseudomonas aeruginosa
Open accessAbstract
Multidrug resistance in Gram-negative bacteria has become so threatening to human health that new antibacterial platforms are desperately needed to combat these deadly infections. The concept of siderophore conjugation, which facilitates compound uptake across the outer membrane by hijacking bacterial iron acquisition systems, has received significant attention in recent years. While standard in vitro MIC and resistance frequency methods demonstrate that these compounds are potent, broad-spectrum antibacterial agents whose activity should not be threatened by unacceptably high spontaneous resistance rates, recapitulation of these results in animal models can prove unreliable, partially because of the differences in iron availability in these different methods. Here, we describe the characterization of MB-1, a novel siderophore-conjugated monobactam that demonstrates excellent in vitro activity against Pseudomonas aeruginosa when tested using standard assay conditions. Unfortunately, the in vitro findings did not correlate with the in vivo results we obtained, as multiple strains were not effectively treated by MB-1 despite having low MICs. To address this, we also describe the development of new in vitro assays that were predictive of efficacy in mouse models, and we provide evidence that competition with native siderophores could contribute to the recalcitrance of some P. aeruginosa isolates in vivo .
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Apart from binding their primary ligand, FeEnt, with high affinity, and its aposiderophore Ent with 100-200-fold lower affinity, KpnFepA_1658, KpnIroN, and KpnFepA_4984 showed different preferences for ferric catecholate complexes and siderophore antibiotics cefiderocol [FeFDC] and FeMB-1.
“Apart from binding their primary ligand, FeEnt, with high affinity, and its aposiderophore Ent with 100-200-fold lower affinity (38), KpnFepA_1658, KpnIroN, and KpnFepA_4984 showed different preferences for ferric catecholate complexes and siderophore antibiotics cefiderocol [FeFDC (40,41)] and FeMB-1 (42,43):”
From Siderophore-mediated iron acquisition by <i>Klebsiella pneumoniae</i> (2024) · cites this paper as [42]
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- Authors
- Tomaras, A. P., Crandon, J. L., McPherson, C. J., Banevicius, M. A., Finegan, S. M., Irvine, R. L., Brown, M. F., O'Donnell, J. P., & Nicolau, D. P.
- Affiliations
- Pfizer (United States) (US)
- Hartford Hospital (US)
- Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA
- Antibacterials Research Unit, Pfizer Worldwide Research and Development, Groton, Connecticut, USA
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2013-09
- Volume
- 57
- Issue
- 9
- Pages
- 4197-4207
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC3754284
- OpenAlex
- W2171062223
- Cited by
- 110
- References
- 39
- Citations by year
- 2025: 4 · 2024: 12 · 2023: 7 · 2022: 7 · 2021: 12 · 2020: 8 · 2019: 12 · 2018: 10 · 2017: 11 · 2016: 9 · 2015: 13 · 2014: 5
- FWCI
- 4.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- Pseudomonas aeruginosa, monobactams, mb-1, multidrug resistance, Gram-negative bacteria, iron acquisition systems, outer membrane permeability, in vitro-in vivo correlation, mouse infection model, antibiotic resistance
- MeSH terms
- Adaptation, Physiological, Animals, Anti-Bacterial Agents, Biological Assay, Female, Iron, Mice, Inbred ICR, Microbial Sensitivity Tests, Monobactams, Oligopeptides, Pseudomonas aeruginosa, Pseudomonas Infections, Pyridones, Mutagenesis, Site-Directed, Treatment Failure, Siderophores, Drug Resistance, Bacterial, Mice
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