Cytoplasmic Delivery of an Antibiotic, Trimethoprim, with a Simple Bidentate Catechol Analog as a Siderophore Mimetic

Do Young Kim, Suyeon Yeom, Jimin Park, Heeyeong Lee, Hak Joong Kim

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Concerns about antibiotic-resistant Gram-negative pathogens are escalating, and accordingly siderophore-based intracellular antibiotic delivery is attracting more attention as an effective means to overcome these infections. Despite the successful clinical translation of this strategy, the delivery potential of siderophores has been limited to periplasm targeting, and this has appreciably restricted the repertoire of applicable antibiotics. To overcome this shortcoming of the current technology, this study focused on investigating the capability of simple bidentate catechol analogs to function as vehicles for cytoplasmic antibiotic delivery. Specifically, by employing trimethoprim, an inhibitor of dihydrofolate reductase located in the cytoplasm, as a model antibiotic, a chemical library of chelator-antibiotic conjugates featuring four different catechol analogs was prepared. Then, their various pharmacological properties and antimicrobial activities were evaluated. Analysis of these characterization data led to the identification of the active conjugates exhibiting notable iron- and trimethoprim-dependent potency against Escherichia coli. Further characterization of these hit molecules using E. coli mutant strains revealed that 2,3-dihydroxybenzoate could effectively deliver several corresponding conjugates to the cytoplasm by exploiting the siderophore uptake machineries present across the outer and inner membranes, originally designated for the native siderophore of E. coli, enterobactin. Considering the synthetic simplicity, such a catechol analog could have appreciable usage in potentiating cytoplasm-active antibiotics against recalcitrant Gram-negative pathogens.

Original languageEnglish
Pages (from-to)554-566
Number of pages13
JournalACS Infectious Diseases
Volume9
Issue number3
DOIs
Publication statusPublished - 2023 Mar 10

Bibliographical note

Funding Information:
This work was supported by a National Research Foundation of Korea (NRF) Grant NRF-2021R1A2C1094331.

Publisher Copyright:
© 2023 American Chemical Society.

Keywords

  • Gram-negative pathogen
  • Siderophore
  • antibiotic resistance
  • cytoplasmic delivery
  • membrane permeability barrier
  • targeted antibiotic delivery

ASJC Scopus subject areas

  • Infectious Diseases

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