The Anti-virulence Efficacy of 4-(1,3-Dimethyl-2,3-Dihydro-1H-Benzimidazol-2-yl)Phenol Against Methicillin-Resistant Staphylococcus aureus
Antimicrobial drug discovery against drug-resistant bacteria is an urgent need. Beyond agents with direct antibacterial activity, anti-virulent molecules may also be viable compounds to defend against bacterial pathogenesis. Using a high throughput screen (HTS) that utilized Caenorhabditis elegans i...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-07-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2019.01557/full |
| _version_ | 1830286149294227456 |
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| author | Nagendran Tharmalingam Rajamohammed Khader Beth Burgwyn Fuchs Eleftherios Mylonakis |
| author_facet | Nagendran Tharmalingam Rajamohammed Khader Beth Burgwyn Fuchs Eleftherios Mylonakis |
| author_sort | Nagendran Tharmalingam |
| collection | DOAJ |
| description | Antimicrobial drug discovery against drug-resistant bacteria is an urgent need. Beyond agents with direct antibacterial activity, anti-virulent molecules may also be viable compounds to defend against bacterial pathogenesis. Using a high throughput screen (HTS) that utilized Caenorhabditis elegans infected with methicillin-resistant Staphylococcus aureus (MRSA) strain of MW2, we identified 4-(1,3-dimethyl-2,3-dihydro-1H-benzimidazol-2-yl)phenol (BIP). Interestingly, BIP had no in vitro inhibition activity against MW2, at least up to 64 μg/ml. The lack of direct antimicrobial activity suggests that BIP could inhibit bacterial virulence factors. To explore the possible anti-virulence effect of the identified molecule, we first performed real-time PCR to examine changes in virulence expression. BIP was highly active against MRSA virulence factors at sub-lethal concentrations and down-regulated virulence regulator genes, such as agrA and codY. However, the benzimidazole derivatives omeprazole and pantoprazole did not down-regulate virulence genes significantly, compared to BIP. Moreover, the BIP-pretreated MW2 cells were more vulnerable to macrophage-mediated killing, as confirmed by intracellular killing and live/dead staining assays, and less efficient in establishing a lethal infection in the invertebrate host Galleria mellonella (p = 0.0131). We tested the cytotoxicity of BIP against human red blood cells (RBCs), and it did not cause hemolysis at the highest concentration tested (64 μg/ml). Taken together, our findings outline the potential anti-virulence activity of BIP that was identified through a C. elegans-based, whole animal based, screen. |
| first_indexed | 2024-12-19T03:52:38Z |
| format | Article |
| id | doaj.art-5addca3b8d654b589f253e9a6b962651 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-19T03:52:38Z |
| publishDate | 2019-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-5addca3b8d654b589f253e9a6b9626512022-12-21T20:36:54ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2019-07-011010.3389/fmicb.2019.01557434660The Anti-virulence Efficacy of 4-(1,3-Dimethyl-2,3-Dihydro-1H-Benzimidazol-2-yl)Phenol Against Methicillin-Resistant Staphylococcus aureusNagendran TharmalingamRajamohammed KhaderBeth Burgwyn FuchsEleftherios MylonakisAntimicrobial drug discovery against drug-resistant bacteria is an urgent need. Beyond agents with direct antibacterial activity, anti-virulent molecules may also be viable compounds to defend against bacterial pathogenesis. Using a high throughput screen (HTS) that utilized Caenorhabditis elegans infected with methicillin-resistant Staphylococcus aureus (MRSA) strain of MW2, we identified 4-(1,3-dimethyl-2,3-dihydro-1H-benzimidazol-2-yl)phenol (BIP). Interestingly, BIP had no in vitro inhibition activity against MW2, at least up to 64 μg/ml. The lack of direct antimicrobial activity suggests that BIP could inhibit bacterial virulence factors. To explore the possible anti-virulence effect of the identified molecule, we first performed real-time PCR to examine changes in virulence expression. BIP was highly active against MRSA virulence factors at sub-lethal concentrations and down-regulated virulence regulator genes, such as agrA and codY. However, the benzimidazole derivatives omeprazole and pantoprazole did not down-regulate virulence genes significantly, compared to BIP. Moreover, the BIP-pretreated MW2 cells were more vulnerable to macrophage-mediated killing, as confirmed by intracellular killing and live/dead staining assays, and less efficient in establishing a lethal infection in the invertebrate host Galleria mellonella (p = 0.0131). We tested the cytotoxicity of BIP against human red blood cells (RBCs), and it did not cause hemolysis at the highest concentration tested (64 μg/ml). Taken together, our findings outline the potential anti-virulence activity of BIP that was identified through a C. elegans-based, whole animal based, screen.https://www.frontiersin.org/article/10.3389/fmicb.2019.01557/fullanti-virulent moleculesagrAbacterial virulencecodYmethicillin-resistant Staphylococcus aureus |
| spellingShingle | Nagendran Tharmalingam Rajamohammed Khader Beth Burgwyn Fuchs Eleftherios Mylonakis The Anti-virulence Efficacy of 4-(1,3-Dimethyl-2,3-Dihydro-1H-Benzimidazol-2-yl)Phenol Against Methicillin-Resistant Staphylococcus aureus Frontiers in Microbiology anti-virulent molecules agrA bacterial virulence codY methicillin-resistant Staphylococcus aureus |
| title | The Anti-virulence Efficacy of 4-(1,3-Dimethyl-2,3-Dihydro-1H-Benzimidazol-2-yl)Phenol Against Methicillin-Resistant Staphylococcus aureus |
| title_full | The Anti-virulence Efficacy of 4-(1,3-Dimethyl-2,3-Dihydro-1H-Benzimidazol-2-yl)Phenol Against Methicillin-Resistant Staphylococcus aureus |
| title_fullStr | The Anti-virulence Efficacy of 4-(1,3-Dimethyl-2,3-Dihydro-1H-Benzimidazol-2-yl)Phenol Against Methicillin-Resistant Staphylococcus aureus |
| title_full_unstemmed | The Anti-virulence Efficacy of 4-(1,3-Dimethyl-2,3-Dihydro-1H-Benzimidazol-2-yl)Phenol Against Methicillin-Resistant Staphylococcus aureus |
| title_short | The Anti-virulence Efficacy of 4-(1,3-Dimethyl-2,3-Dihydro-1H-Benzimidazol-2-yl)Phenol Against Methicillin-Resistant Staphylococcus aureus |
| title_sort | anti virulence efficacy of 4 1 3 dimethyl 2 3 dihydro 1h benzimidazol 2 yl phenol against methicillin resistant staphylococcus aureus |
| topic | anti-virulent molecules agrA bacterial virulence codY methicillin-resistant Staphylococcus aureus |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2019.01557/full |
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