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Conjugation to Enterobactin and Salmochelin S4 Enhances the Antimicrobial Activity and Selectivity of β-Lactam Antibiotics against Nontyphoidal Salmonella

  • Artur Sargun
    Artur Sargun
    Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
    More by Artur Sargun
  • Martina Sassone-Corsi
    Martina Sassone-Corsi
    Department of Microbiology & Molecular Genetics, University of California Irvine, Irvine, California 92697, United States
  • Tengfei Zheng
    Tengfei Zheng
    Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
  • Manuela Raffatellu*
    Manuela Raffatellu
    Department of Microbiology & Molecular Genetics, University of California Irvine, Irvine, California 92697, United States
    Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, California 92093, United States
    Center for Microbiome Innovation, University of California San Diego, La Jolla, California 92093, United States
    Chiba University − UC San Diego Center for Mucosal Immunology, Allergy, and Vaccines, La Jolla, California 92093, United States
    *Email: [email protected]
  • , and 
  • Elizabeth M. Nolan*
    Elizabeth M. Nolan
    Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
    *Email: [email protected]. Phone: 617-452-2495.
Cite this: ACS Infect. Dis. 2021, 7, 5, 1248–1259
Publication Date (Web):March 10, 2021
https://doi.org/10.1021/acsinfecdis.1c00005
Copyright © 2021 American Chemical Society
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Abstract

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The pathogen Salmonella enterica is a leading cause of infection worldwide. Nontyphoidal Salmonella (NTS) serovars typically cause inflammatory diarrhea in healthy individuals, and can cause bacteremia in immunocompromised patients, children, and the elderly. Management of NTS infection poses a challenge because antibiotic treatment prolongs fecal shedding of the pathogen and is thus not recommended for most patients. In recent years, the emergence of antibiotic resistance in NTS has also become a major issue. Thus, new therapeutic strategies to target NTS are needed. Here, we evaluated whether six siderophore-β-lactam conjugates based on enterobactin (Ent) and salmochelin S4 (digulcosylated Ent, DGE) provide antimicrobial activity against the two highly prevalent NTS serovars Typhimurium and Enteritidis by targeting the siderophore receptors FepA and/or IroN. The conjugates showed 10- to 1000-fold lower minimum inhibitory concentrations against both serovars Typhimurium and Enteritidis compared to the parent antibiotics under iron limitation and were recognized and transported by FepA and/or IroN. NTS treated with the Ent/DGE-β-lactam conjugates exhibited aberrant cellular morphologies suggesting inhibition of penicillin-binding proteins, and the conjugates selectively killed NTS in coculture with Staphylococcus aureus. Lastly, the DGE-based conjugates proved to be effective at inhibiting growth of NTS in the presence of the Ent-sequestering protein lipocalin-2. This work describes the successful use of siderophore-antibiotic conjugates against NTS and highlights the opportunity for narrowing the activity spectrum of antibiotics by using Ent and DGE to target enteric bacterial pathogens.

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsinfecdis.1c00005.

  • Supporting Experimental Section, Tables S1–S4, Figures S1–S8 and Supporting References (PDF)

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