Identification of a Small Molecule Anti-biofilm Agent Against Salmonella enterica
Biofilm formation is a common strategy utilized by bacterial pathogens to establish persistence in a host niche. Salmonella enterica serovar Typhi, the etiological agent of Typhoid fever, relies on biofilm formation in the gallbladder to chronically colonize asymptomatic carriers, allowing for trans...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-11-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2018.02804/full |
| _version_ | 1811263907420962816 |
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| author | Jasmine Moshiri Darpan Kaur Chido M. Hambira Jenna L. Sandala Jacob A. Koopman James R. Fuchs John S. Gunn |
| author_facet | Jasmine Moshiri Darpan Kaur Chido M. Hambira Jenna L. Sandala Jacob A. Koopman James R. Fuchs John S. Gunn |
| author_sort | Jasmine Moshiri |
| collection | DOAJ |
| description | Biofilm formation is a common strategy utilized by bacterial pathogens to establish persistence in a host niche. Salmonella enterica serovar Typhi, the etiological agent of Typhoid fever, relies on biofilm formation in the gallbladder to chronically colonize asymptomatic carriers, allowing for transmission to uninfected individuals. S. enterica serovar Typhimurium utilizes biofilms to achieve persistence in human and animal hosts, an issue of both clinical and agricultural importance. Here, we identify a compound that selectively inhibits biofilm formation in both S. Typhi and S. Typhimurium serovars at early stages of biofilm development with an EC50 of 21.0 and 7.4 μM, respectively. We find that this compound, T315, also reduces biofilm formation in Acinetobacter baumannii, a nosocomial and opportunistic pathogen with rising antibiotic resistance. T315 treatment in conjunction with sub-MIC dosing of ciprofloxacin further reduces S. enterica biofilm formation, demonstrating the potential of such combination therapies for therapeutic development. Through synthesis of two biotin-labeled T315 probes and subsequent pull-down and proteomics analysis, we identified a T315 binding target: WrbA, a flavin mononucleotide-dependent NADH:quinone oxidoreductase. Using a S. Typhimurium strain lacking WrbA we demonstrate that this factor contributes to endogenous S. enterica biofilm formation processes and is required for full T315 anti-biofilm activity. We suggest WrbA as a promising target for further development of anti-biofilm agents in Salmonella, with potential for use against additional bacterial pathogens. The development of anti-biofilm therapeutics will be essential to combat chronic carriage of Typhoid fever and thus accomplish a meaningful reduction of global disease burden. |
| first_indexed | 2024-04-12T19:53:36Z |
| format | Article |
| id | doaj.art-b89874455b3e4f0d8b60f3c1cf7ac92d |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-04-12T19:53:36Z |
| publishDate | 2018-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-b89874455b3e4f0d8b60f3c1cf7ac92d2022-12-22T03:18:45ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2018-11-01910.3389/fmicb.2018.02804416555Identification of a Small Molecule Anti-biofilm Agent Against Salmonella entericaJasmine Moshiri0Darpan Kaur1Chido M. Hambira2Jenna L. Sandala3Jacob A. Koopman4James R. Fuchs5John S. Gunn6Department of Microbial Infection and Immunity, Infectious Diseases Institute, The Ohio State University, Columbus, OH, United StatesDepartment of Microbial Infection and Immunity, Infectious Diseases Institute, The Ohio State University, Columbus, OH, United StatesDivision of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, United StatesDepartment of Microbial Infection and Immunity, Infectious Diseases Institute, The Ohio State University, Columbus, OH, United StatesDepartment of Microbial Infection and Immunity, Infectious Diseases Institute, The Ohio State University, Columbus, OH, United StatesDivision of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, United StatesDepartment of Microbial Infection and Immunity, Infectious Diseases Institute, The Ohio State University, Columbus, OH, United StatesBiofilm formation is a common strategy utilized by bacterial pathogens to establish persistence in a host niche. Salmonella enterica serovar Typhi, the etiological agent of Typhoid fever, relies on biofilm formation in the gallbladder to chronically colonize asymptomatic carriers, allowing for transmission to uninfected individuals. S. enterica serovar Typhimurium utilizes biofilms to achieve persistence in human and animal hosts, an issue of both clinical and agricultural importance. Here, we identify a compound that selectively inhibits biofilm formation in both S. Typhi and S. Typhimurium serovars at early stages of biofilm development with an EC50 of 21.0 and 7.4 μM, respectively. We find that this compound, T315, also reduces biofilm formation in Acinetobacter baumannii, a nosocomial and opportunistic pathogen with rising antibiotic resistance. T315 treatment in conjunction with sub-MIC dosing of ciprofloxacin further reduces S. enterica biofilm formation, demonstrating the potential of such combination therapies for therapeutic development. Through synthesis of two biotin-labeled T315 probes and subsequent pull-down and proteomics analysis, we identified a T315 binding target: WrbA, a flavin mononucleotide-dependent NADH:quinone oxidoreductase. Using a S. Typhimurium strain lacking WrbA we demonstrate that this factor contributes to endogenous S. enterica biofilm formation processes and is required for full T315 anti-biofilm activity. We suggest WrbA as a promising target for further development of anti-biofilm agents in Salmonella, with potential for use against additional bacterial pathogens. The development of anti-biofilm therapeutics will be essential to combat chronic carriage of Typhoid fever and thus accomplish a meaningful reduction of global disease burden.https://www.frontiersin.org/article/10.3389/fmicb.2018.02804/fullbiofilmchronic infectionSalmonellaTyphoidanti-biofilm |
| spellingShingle | Jasmine Moshiri Darpan Kaur Chido M. Hambira Jenna L. Sandala Jacob A. Koopman James R. Fuchs John S. Gunn Identification of a Small Molecule Anti-biofilm Agent Against Salmonella enterica Frontiers in Microbiology biofilm chronic infection Salmonella Typhoid anti-biofilm |
| title | Identification of a Small Molecule Anti-biofilm Agent Against Salmonella enterica |
| title_full | Identification of a Small Molecule Anti-biofilm Agent Against Salmonella enterica |
| title_fullStr | Identification of a Small Molecule Anti-biofilm Agent Against Salmonella enterica |
| title_full_unstemmed | Identification of a Small Molecule Anti-biofilm Agent Against Salmonella enterica |
| title_short | Identification of a Small Molecule Anti-biofilm Agent Against Salmonella enterica |
| title_sort | identification of a small molecule anti biofilm agent against salmonella enterica |
| topic | biofilm chronic infection Salmonella Typhoid anti-biofilm |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2018.02804/full |
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