The neutrally charged diarylurea compound PQ401 kills antibiotic-resistant and antibiotic-tolerant Staphylococcus aureus
Resistance or tolerance to traditional antibiotics is a challenging issue in antimicrobial chemotherapy. Moreover, traditional bactericidal antibiotics kill only actively growing bacterial cells, whereas nongrowing metabolically inactive cells are tolerant to and therefore "persist" in the...
| Main Authors: | , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2021
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| Online Access: | https://hdl.handle.net/10356/146178 |
| _version_ | 1811685372555427840 |
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| author | Kim, Wooseong Zou, Guijin Pan, Wen Fricke, Nico Faizi, Hammad A. Kim, Soo Min Khader, Rajamohammed Li, Silei Lee, Kiho Escorba, Iliana Vlahovska, Petia M. Gao, Huajian Ausubel, Frederick M. Mylonakis, Eleftherios |
| author2 | School of Mechanical and Aerospace Engineering |
| author_facet | School of Mechanical and Aerospace Engineering Kim, Wooseong Zou, Guijin Pan, Wen Fricke, Nico Faizi, Hammad A. Kim, Soo Min Khader, Rajamohammed Li, Silei Lee, Kiho Escorba, Iliana Vlahovska, Petia M. Gao, Huajian Ausubel, Frederick M. Mylonakis, Eleftherios |
| author_sort | Kim, Wooseong |
| collection | NTU |
| description | Resistance or tolerance to traditional antibiotics is a challenging issue in antimicrobial chemotherapy. Moreover, traditional bactericidal antibiotics kill only actively growing bacterial cells, whereas nongrowing metabolically inactive cells are tolerant to and therefore "persist" in the presence of legacy antibiotics. Here, we report that the diarylurea derivative PQ401, previously characterized as an inhibitor of the insulin-like growth factor I receptor, kills both antibiotic-resistant and nongrowing antibiotic-tolerant methicillin-resistant Staphylococcus aureus (MRSA) by lipid bilayer disruption. PQ401 showed several beneficial properties as an antimicrobial lead compound, including rapid killing kinetics, low probability for resistance development, high selectivity to bacterial membranes compared to mammalian membranes, and synergism with gentamicin. In contrast to well-studied membrane-disrupting cationic antimicrobial low-molecular-weight compounds and peptides, molecular dynamic simulations supported by efficacy data demonstrate that the neutral form of PQ401 penetrates and subsequently embeds into bacterial lipid bilayers more effectively than the cationic form. Lastly, PQ401 showed efficacy in both the Caenorhabditis elegans and Galleria mellonella models of MRSA infection. These data suggest that PQ401 may be a lead candidate for repurposing as a membrane-active antimicrobial and has potential for further development as a human antibacterial therapeutic for difficult-to-treat infections caused by both drug-resistant and -tolerant S. aureus. |
| first_indexed | 2024-10-01T04:43:29Z |
| format | Journal Article |
| id | ntu-10356/146178 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T04:43:29Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1461782023-03-04T17:12:34Z The neutrally charged diarylurea compound PQ401 kills antibiotic-resistant and antibiotic-tolerant Staphylococcus aureus Kim, Wooseong Zou, Guijin Pan, Wen Fricke, Nico Faizi, Hammad A. Kim, Soo Min Khader, Rajamohammed Li, Silei Lee, Kiho Escorba, Iliana Vlahovska, Petia M. Gao, Huajian Ausubel, Frederick M. Mylonakis, Eleftherios School of Mechanical and Aerospace Engineering High Performance Computing Centre, A*STAR Engineering::Mechanical engineering Persisters Antibiotic Tolerance Resistance or tolerance to traditional antibiotics is a challenging issue in antimicrobial chemotherapy. Moreover, traditional bactericidal antibiotics kill only actively growing bacterial cells, whereas nongrowing metabolically inactive cells are tolerant to and therefore "persist" in the presence of legacy antibiotics. Here, we report that the diarylurea derivative PQ401, previously characterized as an inhibitor of the insulin-like growth factor I receptor, kills both antibiotic-resistant and nongrowing antibiotic-tolerant methicillin-resistant Staphylococcus aureus (MRSA) by lipid bilayer disruption. PQ401 showed several beneficial properties as an antimicrobial lead compound, including rapid killing kinetics, low probability for resistance development, high selectivity to bacterial membranes compared to mammalian membranes, and synergism with gentamicin. In contrast to well-studied membrane-disrupting cationic antimicrobial low-molecular-weight compounds and peptides, molecular dynamic simulations supported by efficacy data demonstrate that the neutral form of PQ401 penetrates and subsequently embeds into bacterial lipid bilayers more effectively than the cationic form. Lastly, PQ401 showed efficacy in both the Caenorhabditis elegans and Galleria mellonella models of MRSA infection. These data suggest that PQ401 may be a lead candidate for repurposing as a membrane-active antimicrobial and has potential for further development as a human antibacterial therapeutic for difficult-to-treat infections caused by both drug-resistant and -tolerant S. aureus. Agency for Science, Technology and Research (A*STAR) Nanyang Technological University Published version This study was supported by National Institutes of Health grant P01AI083214 to F.M.A.and E.M. W.K. is supported by the National Research Foundation of Korea grants funded by the South Korean government (MSIT)(2020R1C1C1008842, 2018R1A5A2025286, and 2017M3A9E4077234). G.Z. and H.G. acknowledge support from a start-up grant from the Nanyang Technological University and Institute of High Performance Computing, A*STAR, Singapore. Molecular dynamics simulations reported were performed on resources of the National Supercomputing Centre, Singapore (http://www.nscc.sg). 2021-01-29T03:59:45Z 2021-01-29T03:59:45Z 2020 Journal Article Kim, W., Zou, G., Pan, W., Fricke, N., Faizi, H. A., Kim, S. M., . . . Mylonakis, E. (2020). The neutrally charged diarylurea compound PQ401 kills antibiotic-resistant and antibiotic-tolerant Staphylococcus aureus. mBio, 11(3), e01140-20-. doi:10.1128/mBio.01140-20 2161-2129 https://hdl.handle.net/10356/146178 10.1128/mBio.01140-20 32605985 2-s2.0-85086500393 3 11 en mBio © 2020 Kim et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. application/pdf |
| spellingShingle | Engineering::Mechanical engineering Persisters Antibiotic Tolerance Kim, Wooseong Zou, Guijin Pan, Wen Fricke, Nico Faizi, Hammad A. Kim, Soo Min Khader, Rajamohammed Li, Silei Lee, Kiho Escorba, Iliana Vlahovska, Petia M. Gao, Huajian Ausubel, Frederick M. Mylonakis, Eleftherios The neutrally charged diarylurea compound PQ401 kills antibiotic-resistant and antibiotic-tolerant Staphylococcus aureus |
| title | The neutrally charged diarylurea compound PQ401 kills antibiotic-resistant and antibiotic-tolerant Staphylococcus aureus |
| title_full | The neutrally charged diarylurea compound PQ401 kills antibiotic-resistant and antibiotic-tolerant Staphylococcus aureus |
| title_fullStr | The neutrally charged diarylurea compound PQ401 kills antibiotic-resistant and antibiotic-tolerant Staphylococcus aureus |
| title_full_unstemmed | The neutrally charged diarylurea compound PQ401 kills antibiotic-resistant and antibiotic-tolerant Staphylococcus aureus |
| title_short | The neutrally charged diarylurea compound PQ401 kills antibiotic-resistant and antibiotic-tolerant Staphylococcus aureus |
| title_sort | neutrally charged diarylurea compound pq401 kills antibiotic resistant and antibiotic tolerant staphylococcus aureus |
| topic | Engineering::Mechanical engineering Persisters Antibiotic Tolerance |
| url | https://hdl.handle.net/10356/146178 |
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