Discovery of an antivirulence compound that reverses β-lactam resistance in MRSA
Staphylococcus aureus is the leading cause of infections worldwide, and methicillin-resistant strains (MRSA) are emerging. New strategies are urgently needed to overcome this threat. Using a cell-based screen of ~45,000 diverse synthetic compounds, we discovered a potent bioactive, MAC-545496, that...
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| Veröffentlicht in: | Nature chemical biology 2020-02, Vol.16 (2), p.143-149 |
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| creator | El-Halfawy, Omar M. Czarny, Tomasz L. Flannagan, Ronald S. Day, Jonathan Bozelli, José Carlos Kuiack, Robert C. Salim, Ahmed Eckert, Philip Epand, Richard M. McGavin, Martin J. Organ, Michael G. Heinrichs, David E. Brown, Eric D. |
| description | Staphylococcus aureus
is the leading cause of infections worldwide, and methicillin-resistant strains (MRSA) are emerging. New strategies are urgently needed to overcome this threat. Using a cell-based screen of ~45,000 diverse synthetic compounds, we discovered a potent bioactive, MAC-545496, that reverses
β
-lactam resistance in the community-acquired MRSA USA300 strain. MAC-545496 could also serve as an antivirulence agent alone; it attenuates MRSA virulence in
Galleria mellonella
larvae. MAC-545496 inhibits biofilm formation and abrogates intracellular survival in macrophages. Mechanistic characterization revealed MAC-545496 to be a nanomolar inhibitor of GraR, a regulator that responds to cell-envelope stress and is an important virulence factor and determinant of antibiotic resistance. The small molecule discovered herein is an inhibitor of GraR function. MAC-545496 has value as a research tool to probe the GraXRS regulatory system and as an antibacterial lead series of a mechanism to combat drug-resistant Staphylococcal infections.
A potent inhibitor of the MRSA virulence regulator, GraR, reverses methicillin resistance, inhibits biofilm formation, limits bacterial survival in macrophages and attenuates virulence in vitro, synergizing with cationic antimicrobial peptides. |
| doi_str_mv | 10.1038/s41589-019-0401-8 |
| format | Article |
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is the leading cause of infections worldwide, and methicillin-resistant strains (MRSA) are emerging. New strategies are urgently needed to overcome this threat. Using a cell-based screen of ~45,000 diverse synthetic compounds, we discovered a potent bioactive, MAC-545496, that reverses
β
-lactam resistance in the community-acquired MRSA USA300 strain. MAC-545496 could also serve as an antivirulence agent alone; it attenuates MRSA virulence in
Galleria mellonella
larvae. MAC-545496 inhibits biofilm formation and abrogates intracellular survival in macrophages. Mechanistic characterization revealed MAC-545496 to be a nanomolar inhibitor of GraR, a regulator that responds to cell-envelope stress and is an important virulence factor and determinant of antibiotic resistance. The small molecule discovered herein is an inhibitor of GraR function. MAC-545496 has value as a research tool to probe the GraXRS regulatory system and as an antibacterial lead series of a mechanism to combat drug-resistant Staphylococcal infections.
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is the leading cause of infections worldwide, and methicillin-resistant strains (MRSA) are emerging. New strategies are urgently needed to overcome this threat. Using a cell-based screen of ~45,000 diverse synthetic compounds, we discovered a potent bioactive, MAC-545496, that reverses
β
-lactam resistance in the community-acquired MRSA USA300 strain. MAC-545496 could also serve as an antivirulence agent alone; it attenuates MRSA virulence in
Galleria mellonella
larvae. MAC-545496 inhibits biofilm formation and abrogates intracellular survival in macrophages. Mechanistic characterization revealed MAC-545496 to be a nanomolar inhibitor of GraR, a regulator that responds to cell-envelope stress and is an important virulence factor and determinant of antibiotic resistance. The small molecule discovered herein is an inhibitor of GraR function. MAC-545496 has value as a research tool to probe the GraXRS regulatory system and as an antibacterial lead series of a mechanism to combat drug-resistant Staphylococcal infections.
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is the leading cause of infections worldwide, and methicillin-resistant strains (MRSA) are emerging. New strategies are urgently needed to overcome this threat. Using a cell-based screen of ~45,000 diverse synthetic compounds, we discovered a potent bioactive, MAC-545496, that reverses
β
-lactam resistance in the community-acquired MRSA USA300 strain. MAC-545496 could also serve as an antivirulence agent alone; it attenuates MRSA virulence in
Galleria mellonella
larvae. MAC-545496 inhibits biofilm formation and abrogates intracellular survival in macrophages. Mechanistic characterization revealed MAC-545496 to be a nanomolar inhibitor of GraR, a regulator that responds to cell-envelope stress and is an important virulence factor and determinant of antibiotic resistance. The small molecule discovered herein is an inhibitor of GraR function. MAC-545496 has value as a research tool to probe the GraXRS regulatory system and as an antibacterial lead series of a mechanism to combat drug-resistant Staphylococcal infections.
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| fulltext | fulltext |
| identifier | ISSN: 1552-4450 |
| ispartof | Nature chemical biology, 2020-02, Vol.16 (2), p.143-149 |
| issn | 1552-4450 1552-4469 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2318729553 |
| source | MEDLINE; Nature Journals Online; SpringerLink Journals - AutoHoldings |
| subjects | 631/154/1435/2163 631/154/555 631/326/41 631/92/93 Amides Animals Anti-Bacterial Agents - pharmacology Antibiotic resistance Antibiotics Antiinfectives and antibacterials Antimicrobial peptides beta-Lactam Resistance - drug effects Biochemical Engineering Biochemistry Biofilms Biofilms - drug effects Bioorganic Chemistry Cationic antimicrobial peptides Cell Biology Chemistry Chemistry and Materials Science Chemistry/Food Science Drug resistance High-Throughput Screening Assays - methods Inhibitors Larva - microbiology Larvae Lepidoptera - microbiology Macrophages Methicillin Methicillin-Resistant Staphylococcus aureus - drug effects Methicillin-Resistant Staphylococcus aureus - pathogenicity Mice Microbial Sensitivity Tests Peptides Piperidines - pharmacology Pyridines - pharmacology RAW 264.7 Cells Staphylococcal Infections - drug therapy Staphylococcal Infections - microbiology Staphylococcus aureus Staphylococcus infections Survival Virulence Virulence factors Virulence Factors - antagonists & inhibitors β-Lactam antibiotics |
| title | Discovery of an antivirulence compound that reverses β-lactam resistance in MRSA |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-06T01%3A51%3A36IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Discovery%20of%20an%20antivirulence%20compound%20that%20reverses%20%CE%B2-lactam%20resistance%20in%20MRSA&rft.jtitle=Nature%20chemical%20biology&rft.au=El-Halfawy,%20Omar%20M.&rft.date=2020-02-01&rft.volume=16&rft.issue=2&rft.spage=143&rft.epage=149&rft.pages=143-149&rft.issn=1552-4450&rft.eissn=1552-4469&rft_id=info:doi/10.1038/s41589-019-0401-8&rft_dat=%3Cproquest_cross%3E2476793816%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2344205119&rft_id=info:pmid/31768032&rfr_iscdi=true |