Identification of a Host-Targeted Compound to Control Typhoid Fever
ABSTRACT Typhoid fever is caused primarily by the enteric microbe Salmonella enterica serovar Typhi and remains a major global health problem with approximately 14 million new infections and 136,000 fatalities annually. While there are antibiotic options available to treat the disease, the global in...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-06-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.00619-22 |
| _version_ | 1818255488681246720 |
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| author | Ky V. Hoang Katherine Woolard Ching Yang Christian Melander John S. Gunn |
| author_facet | Ky V. Hoang Katherine Woolard Ching Yang Christian Melander John S. Gunn |
| author_sort | Ky V. Hoang |
| collection | DOAJ |
| description | ABSTRACT Typhoid fever is caused primarily by the enteric microbe Salmonella enterica serovar Typhi and remains a major global health problem with approximately 14 million new infections and 136,000 fatalities annually. While there are antibiotic options available to treat the disease, the global increase in multidrug-resistant strains necessitates alternative therapeutic options. Host-targeted therapeutics present a promising anti-infective strategy against intracellular bacterial pathogens. A cell-based assay identified a compound that inhibits Salmonella proliferation in infected cells, 2-(3-hydroxypropyl)-1-(3-phenoxyphenyl)-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione (KH-1), which is devoid of direct activity against Salmonella. The compound inhibits the growth of both antibiotic-sensitive and -resistant Salmonella strains inside macrophages and reduces lactate dehydrogenase (LDH) release from Salmonella-infected cells. Subsequent screening of KH-1 commercial analogs identified 2-(4-fluorobenzyl)-1-(3-phenoxyphenyl)-1,2-dihydrochromeno[2,3-c] pyrrole-3,9-dione (KH-1-2), which is more effective in controlling Salmonella growth inside macrophages. In vitro KH-1-2 treatment of Salmonella infection resulted in an 8- to 10-fold reduction in bacterial load in infected macrophages. In combination with suboptimal ciprofloxacin treatment, KH-1-2 further reduces Salmonella growth inside macrophages. The toxicity and efficacy of KH-1-2 in controlling Salmonella infection were examined in vivo using a mouse model of typhoid fever. No significant compound-related clinical signs and histological findings of the liver, spleen, or kidney were observed from uninfected mice that were intraperitoneally treated with KH-1-2. KH-1-2 significantly protected mice from a lethal dose of infection by an antibiotic-resistant Salmonella strain. Thus, our study provides support that this is a promising lead compound for the development of a novel host-targeted therapeutic agent to control typhoid fever. IMPORTANCE Salmonella spp. cause significant morbidity and mortality worldwide. Typhoidal spp. (e.g., S. Typhi) cause a systemic disease typically treated with antibiotics. However, growing antibiotic resistance is resulting in increased treatment failures. We screened a compound library for those that would reduce Salmonella-induced macrophage toxicity, identifying compound KH-1. KH-1 has no direct effects on the bacteria but limits Salmonella survival in macrophages and protects against lethal infection in a mouse model of typhoid fever. A suboptimal concentration of ciprofloxacin worked in conjunction with the compound to further decrease Salmonella survival in macrophages. An analog (KH-1-2) was identified that possessed increased activity in vitro in macrophages and in vivo against both antibiotic-sensitive and -resistant strains. Thus, we report the identification of a lead compound that may be a useful scaffold as a host-directed antimicrobial against typhoid fever. |
| first_indexed | 2024-12-12T17:12:40Z |
| format | Article |
| id | doaj.art-81f808c0da94400e97c0756e5db9d48c |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-12-12T17:12:40Z |
| publishDate | 2022-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-81f808c0da94400e97c0756e5db9d48c2022-12-22T00:17:51ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972022-06-0110310.1128/spectrum.00619-22Identification of a Host-Targeted Compound to Control Typhoid FeverKy V. Hoang0Katherine Woolard1Ching Yang2Christian Melander3John S. Gunn4Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USADepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USACenter for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USADepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USACenter for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USAABSTRACT Typhoid fever is caused primarily by the enteric microbe Salmonella enterica serovar Typhi and remains a major global health problem with approximately 14 million new infections and 136,000 fatalities annually. While there are antibiotic options available to treat the disease, the global increase in multidrug-resistant strains necessitates alternative therapeutic options. Host-targeted therapeutics present a promising anti-infective strategy against intracellular bacterial pathogens. A cell-based assay identified a compound that inhibits Salmonella proliferation in infected cells, 2-(3-hydroxypropyl)-1-(3-phenoxyphenyl)-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione (KH-1), which is devoid of direct activity against Salmonella. The compound inhibits the growth of both antibiotic-sensitive and -resistant Salmonella strains inside macrophages and reduces lactate dehydrogenase (LDH) release from Salmonella-infected cells. Subsequent screening of KH-1 commercial analogs identified 2-(4-fluorobenzyl)-1-(3-phenoxyphenyl)-1,2-dihydrochromeno[2,3-c] pyrrole-3,9-dione (KH-1-2), which is more effective in controlling Salmonella growth inside macrophages. In vitro KH-1-2 treatment of Salmonella infection resulted in an 8- to 10-fold reduction in bacterial load in infected macrophages. In combination with suboptimal ciprofloxacin treatment, KH-1-2 further reduces Salmonella growth inside macrophages. The toxicity and efficacy of KH-1-2 in controlling Salmonella infection were examined in vivo using a mouse model of typhoid fever. No significant compound-related clinical signs and histological findings of the liver, spleen, or kidney were observed from uninfected mice that were intraperitoneally treated with KH-1-2. KH-1-2 significantly protected mice from a lethal dose of infection by an antibiotic-resistant Salmonella strain. Thus, our study provides support that this is a promising lead compound for the development of a novel host-targeted therapeutic agent to control typhoid fever. IMPORTANCE Salmonella spp. cause significant morbidity and mortality worldwide. Typhoidal spp. (e.g., S. Typhi) cause a systemic disease typically treated with antibiotics. However, growing antibiotic resistance is resulting in increased treatment failures. We screened a compound library for those that would reduce Salmonella-induced macrophage toxicity, identifying compound KH-1. KH-1 has no direct effects on the bacteria but limits Salmonella survival in macrophages and protects against lethal infection in a mouse model of typhoid fever. A suboptimal concentration of ciprofloxacin worked in conjunction with the compound to further decrease Salmonella survival in macrophages. An analog (KH-1-2) was identified that possessed increased activity in vitro in macrophages and in vivo against both antibiotic-sensitive and -resistant strains. Thus, we report the identification of a lead compound that may be a useful scaffold as a host-directed antimicrobial against typhoid fever.https://journals.asm.org/doi/10.1128/spectrum.00619-22KH-1-2host-targeted therapytyphoid feverimmunomodulationSalmonella Typhi |
| spellingShingle | Ky V. Hoang Katherine Woolard Ching Yang Christian Melander John S. Gunn Identification of a Host-Targeted Compound to Control Typhoid Fever Microbiology Spectrum KH-1-2 host-targeted therapy typhoid fever immunomodulation Salmonella Typhi |
| title | Identification of a Host-Targeted Compound to Control Typhoid Fever |
| title_full | Identification of a Host-Targeted Compound to Control Typhoid Fever |
| title_fullStr | Identification of a Host-Targeted Compound to Control Typhoid Fever |
| title_full_unstemmed | Identification of a Host-Targeted Compound to Control Typhoid Fever |
| title_short | Identification of a Host-Targeted Compound to Control Typhoid Fever |
| title_sort | identification of a host targeted compound to control typhoid fever |
| topic | KH-1-2 host-targeted therapy typhoid fever immunomodulation Salmonella Typhi |
| url | https://journals.asm.org/doi/10.1128/spectrum.00619-22 |
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