Conjugation to Enterobactin and Salmochelin S4 Enhances the Antimicrobial Activity and Selectivity of β-Lactam Antibiotics against Nontyphoidal Salmonella
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 chal...
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| Format: | Article |
| Language: | English |
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American Chemical Society (ACS)
2022
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| Online Access: | https://hdl.handle.net/1721.1/142537.2 |
| _version_ | 1811096367976677376 |
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| author | Sargun, Artur Sassone-Corsi, Martina Zheng, Tengfei Raffatellu, Manuela Nolan, Elizabeth M. |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Sargun, Artur Sassone-Corsi, Martina Zheng, Tengfei Raffatellu, Manuela Nolan, Elizabeth M. |
| author_sort | Sargun, Artur |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T16:42:42Z |
| format | Article |
| id | mit-1721.1/142537.2 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T16:42:42Z |
| publishDate | 2022 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/142537.22024-03-14T17:34:52Z Conjugation to Enterobactin and Salmochelin S4 Enhances the Antimicrobial Activity and Selectivity of β-Lactam Antibiotics against Nontyphoidal Salmonella Sargun, Artur Sassone-Corsi, Martina Zheng, Tengfei Raffatellu, Manuela Nolan, Elizabeth M. Massachusetts Institute of Technology. Department of Chemistry Infectious Diseases 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. 2022-05-16T19:15:43Z 2022-05-16T14:44:03Z 2022-05-16T19:15:43Z 2021-03 2021-01 2022-05-16T14:32:00Z Article http://purl.org/eprint/type/JournalArticle 2373-8227 https://hdl.handle.net/1721.1/142537.2 Sargun, Artur, Sassone-Corsi, Martina, Zheng, Tengfei, Raffatellu, Manuela and Nolan, Elizabeth M. 2021. "Conjugation to Enterobactin and Salmochelin S4 Enhances the Antimicrobial Activity and Selectivity of β-Lactam Antibiotics against Nontyphoidal Salmonella." ACS Infectious Diseases, 7 (5). en http://dx.doi.org/10.1021/acsinfecdis.1c00005 ACS Infectious Diseases Attribution-NonCommercial-ShareAlike 4.0 International https://creativecommons.org/licenses/by-nc-sa/4.0/ application/octet-stream American Chemical Society (ACS) PMC |
| spellingShingle | Infectious Diseases Sargun, Artur Sassone-Corsi, Martina Zheng, Tengfei Raffatellu, Manuela Nolan, Elizabeth M. Conjugation to Enterobactin and Salmochelin S4 Enhances the Antimicrobial Activity and Selectivity of β-Lactam Antibiotics against Nontyphoidal Salmonella |
| title | Conjugation to Enterobactin and Salmochelin S4 Enhances the Antimicrobial Activity and Selectivity of β-Lactam Antibiotics against Nontyphoidal Salmonella |
| title_full | Conjugation to Enterobactin and Salmochelin S4 Enhances the Antimicrobial Activity and Selectivity of β-Lactam Antibiotics against Nontyphoidal Salmonella |
| title_fullStr | Conjugation to Enterobactin and Salmochelin S4 Enhances the Antimicrobial Activity and Selectivity of β-Lactam Antibiotics against Nontyphoidal Salmonella |
| title_full_unstemmed | Conjugation to Enterobactin and Salmochelin S4 Enhances the Antimicrobial Activity and Selectivity of β-Lactam Antibiotics against Nontyphoidal Salmonella |
| title_short | Conjugation to Enterobactin and Salmochelin S4 Enhances the Antimicrobial Activity and Selectivity of β-Lactam Antibiotics against Nontyphoidal Salmonella |
| title_sort | conjugation to enterobactin and salmochelin s4 enhances the antimicrobial activity and selectivity of β lactam antibiotics against nontyphoidal salmonella |
| topic | Infectious Diseases |
| url | https://hdl.handle.net/1721.1/142537.2 |
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