Targeting virulence: salmochelin modification tunes the antibacterial activity spectrum of β-lactams for pathogen-selective killing of Escherichia coli
New antibiotics are required to treat bacterial infections and counteract the emergence of antibiotic resistance. Pathogen-specific antibiotics have several advantages over broad-spectrum drugs, which include minimal perturbation to the commensal microbiota. We present a strategy for targeting antib...
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| Format: | Article |
| Language: | en_US |
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Royal Society of Chemistry
2016
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| Online Access: | http://hdl.handle.net/1721.1/104034 https://orcid.org/0000-0002-6153-8803 https://orcid.org/0000-0002-5356-3638 |
| _version_ | 1811078690909454336 |
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| author | Chairatana, Phoom Zheng, Tengfei Nolan, Elizabeth Marie |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Chairatana, Phoom Zheng, Tengfei Nolan, Elizabeth Marie |
| author_sort | Chairatana, Phoom |
| collection | MIT |
| description | New antibiotics are required to treat bacterial infections and counteract the emergence of antibiotic resistance. Pathogen-specific antibiotics have several advantages over broad-spectrum drugs, which include minimal perturbation to the commensal microbiota. We present a strategy for targeting antibiotics to bacterial pathogens that utilises the salmochelin-mediated iron uptake machinery of Gram-negative Escherichia coli. Salmochelins are C-glucosylated derivatives of the siderophore enterobactin. The biosynthesis and utilisation of salmochelins are important for virulence because these siderophores allow pathogens to acquire iron and evade the enterobactin-scavenging host-defense protein lipocalin-2. Inspired by the salmochelins, we report the design and chemoenzymatic preparation of glucosylated enterobactin–β-lactam conjugates that harbour the antibiotics ampicillin (Amp) and amoxicillin (Amx), hereafter GlcEnt–Amp/Amx. The GlcEnt scaffolds are based on mono- and diglucosylated Ent where one catechol moiety is functionalized at the C5 position for antibiotic attachment. We demonstrate that GlcEnt–Amp/Amx provide up to 1000-fold enhanced antimicrobial activity against uropathogenic E. coli relative to the parent β-lactams. Moreover, GlcEnt–Amp/Amx based on a diglucosylated Ent (DGE) platform selectively kill uropathogenic E. coli that express the salmochelin receptor IroN in the presence of non-pathogenic E. coli and other bacterial strains that include the commensal microbe Lactobacillus rhamnosus GG. Moreover, GlcEnt–Amp/Amx evade the host-defense protein lipocalin-2, and exhibit low toxicity to mammalian cells. Our work establishes that siderophore–antibiotic conjugates provide a strategy for targeting virulence, narrowing the activity spectrum of antibiotics in clinical use, and achieving selective delivery of antibacterial cargos to pathogenic bacteria on the basis of siderophore receptor expression. |
| first_indexed | 2024-09-23T11:03:36Z |
| format | Article |
| id | mit-1721.1/104034 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:03:36Z |
| publishDate | 2016 |
| publisher | Royal Society of Chemistry |
| record_format | dspace |
| spelling | mit-1721.1/1040342022-10-01T00:54:55Z Targeting virulence: salmochelin modification tunes the antibacterial activity spectrum of β-lactams for pathogen-selective killing of Escherichia coli Chairatana, Phoom Zheng, Tengfei Nolan, Elizabeth Marie Massachusetts Institute of Technology. Department of Chemistry Chairatana, Phoom Zheng, Tengfei Nolan, Elizabeth Marie New antibiotics are required to treat bacterial infections and counteract the emergence of antibiotic resistance. Pathogen-specific antibiotics have several advantages over broad-spectrum drugs, which include minimal perturbation to the commensal microbiota. We present a strategy for targeting antibiotics to bacterial pathogens that utilises the salmochelin-mediated iron uptake machinery of Gram-negative Escherichia coli. Salmochelins are C-glucosylated derivatives of the siderophore enterobactin. The biosynthesis and utilisation of salmochelins are important for virulence because these siderophores allow pathogens to acquire iron and evade the enterobactin-scavenging host-defense protein lipocalin-2. Inspired by the salmochelins, we report the design and chemoenzymatic preparation of glucosylated enterobactin–β-lactam conjugates that harbour the antibiotics ampicillin (Amp) and amoxicillin (Amx), hereafter GlcEnt–Amp/Amx. The GlcEnt scaffolds are based on mono- and diglucosylated Ent where one catechol moiety is functionalized at the C5 position for antibiotic attachment. We demonstrate that GlcEnt–Amp/Amx provide up to 1000-fold enhanced antimicrobial activity against uropathogenic E. coli relative to the parent β-lactams. Moreover, GlcEnt–Amp/Amx based on a diglucosylated Ent (DGE) platform selectively kill uropathogenic E. coli that express the salmochelin receptor IroN in the presence of non-pathogenic E. coli and other bacterial strains that include the commensal microbe Lactobacillus rhamnosus GG. Moreover, GlcEnt–Amp/Amx evade the host-defense protein lipocalin-2, and exhibit low toxicity to mammalian cells. Our work establishes that siderophore–antibiotic conjugates provide a strategy for targeting virulence, narrowing the activity spectrum of antibiotics in clinical use, and achieving selective delivery of antibacterial cargos to pathogenic bacteria on the basis of siderophore receptor expression. Massachusetts Institute of Technology. Department of Chemistry National Institutes of Health (U.S.) (Pacific Southwest Research Center of Excellence for Biodefense and Emerging Infectious Disease) Kinship Foundation. Searle Scholars Program Royal Thai Government (RTG) (Scholarship program) 2016-08-26T16:20:58Z 2016-08-26T16:20:58Z 2015-05 2015-03 Article http://purl.org/eprint/type/JournalArticle 2041-6520 2041-6539 http://hdl.handle.net/1721.1/104034 Chairatana, Phoom, Tengfei, Zheng, and Elizabeth M. Nolan. "Targeting virulence: salmochelin modification tunes the antibacterial activity spectrum of β-lactams for pathogen-selective killing of Escherichia coli." Chemical Science 6 (2015), pp.4458-4471. © Royal Society of Chemistry 2016. https://orcid.org/0000-0002-6153-8803 https://orcid.org/0000-0002-5356-3638 en_US http://dx.doi.org/10.1039/c5sc00962f Chemical Science Creative Commons Attribution-NonCommercial 3.0 Unported licence http://creativecommons.org/licenses/by-nc/3.0/ application/pdf Royal Society of Chemistry Royal Society of Chemistry |
| spellingShingle | Chairatana, Phoom Zheng, Tengfei Nolan, Elizabeth Marie Targeting virulence: salmochelin modification tunes the antibacterial activity spectrum of β-lactams for pathogen-selective killing of Escherichia coli |
| title | Targeting virulence: salmochelin modification tunes the antibacterial activity spectrum of β-lactams for pathogen-selective killing of Escherichia coli |
| title_full | Targeting virulence: salmochelin modification tunes the antibacterial activity spectrum of β-lactams for pathogen-selective killing of Escherichia coli |
| title_fullStr | Targeting virulence: salmochelin modification tunes the antibacterial activity spectrum of β-lactams for pathogen-selective killing of Escherichia coli |
| title_full_unstemmed | Targeting virulence: salmochelin modification tunes the antibacterial activity spectrum of β-lactams for pathogen-selective killing of Escherichia coli |
| title_short | Targeting virulence: salmochelin modification tunes the antibacterial activity spectrum of β-lactams for pathogen-selective killing of Escherichia coli |
| title_sort | targeting virulence salmochelin modification tunes the antibacterial activity spectrum of β lactams for pathogen selective killing of escherichia coli |
| url | http://hdl.handle.net/1721.1/104034 https://orcid.org/0000-0002-6153-8803 https://orcid.org/0000-0002-5356-3638 |
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