Location, Location, Location: Establishing Design Principles for New Antibacterials from Ferric Siderophore Transport Systems

Autor: Vivien Canran Luo, Mark W. Peczuh
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Molecules, Vol 29, Iss 16, p 3889 (2024)
Druh dokumentu: article
ISSN: 29163889
1420-3049
DOI: 10.3390/molecules29163889
Popis: This review strives to assemble a set of molecular design principles that enables the delivery of antibiotic warheads to Gram-negative bacterial targets (ESKAPE pathogens) using iron-chelating siderophores, known as the Trojan Horse strategy for antibiotic development. Principles are derived along two main lines. First, archetypical siderophores and their conjugates are used as case studies for native iron transport. They enable the consideration of the correspondence of iron transport and antibacterial target location. The second line of study charts the rationale behind the clinical antibiotic cefiderocol. It illustrates the potential versatility for the design of new Trojan Horse-based antibiotics. Themes such as matching the warhead to a location where the siderophore delivers its cargo (i.e., periplasm vs. cytoplasm), whether or not a cleavable linker is required, and the relevance of cheaters to the effectiveness and selectivity of new conjugates will be explored. The effort to articulate rules has identified gaps in the current understanding of iron transport pathways and suggests directions for new investigations.
Databáze: Directory of Open Access Journals
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