Potentiation of Antibacterial Activity of the MB-1 Siderophore-Monobactam Conjugate Using an Efflux Pump Inhibitor
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Preliminary enthusiasm over the encouraging spectrum and in vitro activities of siderophore conjugates, such as MB-1, was recently tempered by unexpected variability in in vivo efficacy. The need for these conjugates to compete for iron with endogenously produced siderophores has exposed a significant liability for this novel antibacterial strategy. Here, we have exploited dependence on efflux for siderophore secretion in Pseudomonas aeruginosa and provide evidence that efflux inhibition may circumvent this in vivo -relevant resistance liability.
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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 [43]
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- Authors
- Tomaras, A. P., Crandon, J. L., McPherson, C. J., & Nicolau, D. P.
- Affiliations
- Pfizer (United States) (US)
- Hartford Hospital (US)
- ORCID
- Nicolau, David P.
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 2015-04
- Volume
- 59
- Issue
- 4
- Pages
- 2439-2442
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC4356814
- OpenAlex
- W2089873723
- Cited by
- 32
- References
- 18
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 4 · 2020: 2 · 2019: 4 · 2018: 3 · 2017: 2 · 2016: 4 · 2015: 2
- FWCI
- 1.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- mb-1, efflux pump inhibitors, Pseudomonas aeruginosa, siderophore secretion, iron acquisition, antibacterial activity, in vivo efficacy
- MeSH terms
- Anti-Bacterial Agents, Microbial Sensitivity Tests, Monobactams, Mutation, Pseudomonas aeruginosa, Pyridones, Reserpine, Siderophores, ATP-Binding Cassette Transporters, Drug Resistance, Bacterial
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