Pharmacological Inhibition of the ClpXP Protease Increases Bacterial Susceptibility to Host Cathelicidin Antimicrobial Peptides and Cell Envelope-Active Antibiotics
The ClpXP protease is a critical bacterial intracellular protease that regulates protein turnover in many bacterial species. Here we identified a pharmacological inhibitor of the ClpXP protease, F2, and evaluated its action in Bacillus anthracis and Staphylococcus aureus. We found that F2 exhibited...
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| Veröffentlicht in: | Antimicrobial Agents and Chemotherapy 2012-04, Vol.56 (4), p.1854-1861 |
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| container_title | Antimicrobial Agents and Chemotherapy |
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| creator | McGillivray, Shauna M Tran, Dan N Ramadoss, Nitya S Alumasa, John N Okumura, Cheryl Y Sakoulas, George Vaughn, Micah M Zhang, Dawn X Keiler, Kenneth C Nizet, Victor |
| description | The ClpXP protease is a critical bacterial intracellular protease that regulates protein turnover in many bacterial species. Here we identified a pharmacological inhibitor of the ClpXP protease, F2, and evaluated its action in Bacillus anthracis and Staphylococcus aureus. We found that F2 exhibited synergistic antimicrobial activity with cathelicidin antimicrobial peptides and antibiotics that target the cell well and/or cell membrane, such as penicillin and daptomycin, in B. anthracis and drug-resistant strains of S. aureus. ClpXP inhibition represents a novel therapeutic strategy to simultaneously sensitize pathogenic bacteria to host defenses and pharmaceutical antibiotics. |
| doi_str_mv | 10.1128/aac.05131-11 |
| format | Article |
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Here we identified a pharmacological inhibitor of the ClpXP protease, F2, and evaluated its action in Bacillus anthracis and Staphylococcus aureus. We found that F2 exhibited synergistic antimicrobial activity with cathelicidin antimicrobial peptides and antibiotics that target the cell well and/or cell membrane, such as penicillin and daptomycin, in B. anthracis and drug-resistant strains of S. aureus. ClpXP inhibition represents a novel therapeutic strategy to simultaneously sensitize pathogenic bacteria to host defenses and pharmaceutical antibiotics.</description><identifier>ISSN: 0066-4804</identifier><identifier>EISSN: 1098-6596</identifier><identifier>DOI: 10.1128/aac.05131-11</identifier><identifier>PMID: 22252821</identifier><identifier>CODEN: AACHAX</identifier><language>eng</language><publisher>Washington, DC: American Society for Microbiology</publisher><subject>Amino Acid Sequence ; antagonists & inhibitors ; Anti-Bacterial Agents ; Anti-Bacterial Agents - pharmacology ; antibiotic resistance ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antimicrobial Cationic Peptides ; Antimicrobial Cationic Peptides - pharmacology ; antimicrobial peptides ; antimicrobial properties ; Bacillus anthracis ; Bacillus anthracis - drug effects ; Bacillus anthracis - genetics ; Bacteria ; Bacteria - drug effects ; Biological and medical sciences ; Cell Membrane ; Cell Membrane - metabolism ; cell membranes ; daptomycin ; drug effects ; Drug Resistance, Bacterial ; Drug Synergism ; Endopeptidase Clp ; Endopeptidase Clp - antagonists & inhibitors ; enzyme inhibitors ; Escherichia coli Proteins ; Escherichia coli Proteins - antagonists & inhibitors ; Experimental Therapeutics ; genetics ; growth & development ; Medical sciences ; metabolism ; Methicillin-Resistant Staphylococcus aureus ; Methicillin-Resistant Staphylococcus aureus - drug effects ; Molecular Sequence Data ; pharmacology ; Pharmacology. Drug treatments ; Protease Inhibitors ; Protease Inhibitors - pharmacology ; protein metabolism ; proteinases ; Staphylococcus aureus ; Staphylococcus aureus - drug effects ; Staphylococcus aureus - growth & development ; strains ; synergism ; Tetrazoles ; Tetrazoles - pharmacology</subject><ispartof>Antimicrobial Agents and Chemotherapy, 2012-04, Vol.56 (4), p.1854-1861</ispartof><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012, American Society for Microbiology. All Rights Reserved.</rights><rights>Copyright © 2012, American Society for Microbiology. All Rights Reserved. 2012 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a596t-96a9f697c3cf28a56f86656f8649e34e0331e4fe9d2f3b8d448f84f15bb4fc723</citedby><cites>FETCH-LOGICAL-a596t-96a9f697c3cf28a56f86656f8649e34e0331e4fe9d2f3b8d448f84f15bb4fc723</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318395/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318395/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25696751$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22252821$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McGillivray, Shauna M</creatorcontrib><creatorcontrib>Tran, Dan N</creatorcontrib><creatorcontrib>Ramadoss, Nitya S</creatorcontrib><creatorcontrib>Alumasa, John N</creatorcontrib><creatorcontrib>Okumura, Cheryl Y</creatorcontrib><creatorcontrib>Sakoulas, George</creatorcontrib><creatorcontrib>Vaughn, Micah M</creatorcontrib><creatorcontrib>Zhang, Dawn X</creatorcontrib><creatorcontrib>Keiler, Kenneth C</creatorcontrib><creatorcontrib>Nizet, Victor</creatorcontrib><title>Pharmacological Inhibition of the ClpXP Protease Increases Bacterial Susceptibility to Host Cathelicidin Antimicrobial Peptides and Cell Envelope-Active Antibiotics</title><title>Antimicrobial Agents and Chemotherapy</title><addtitle>Antimicrob Agents Chemother</addtitle><addtitle>Antimicrob Agents Chemother</addtitle><description>The ClpXP protease is a critical bacterial intracellular protease that regulates protein turnover in many bacterial species. Here we identified a pharmacological inhibitor of the ClpXP protease, F2, and evaluated its action in Bacillus anthracis and Staphylococcus aureus. We found that F2 exhibited synergistic antimicrobial activity with cathelicidin antimicrobial peptides and antibiotics that target the cell well and/or cell membrane, such as penicillin and daptomycin, in B. anthracis and drug-resistant strains of S. aureus. ClpXP inhibition represents a novel therapeutic strategy to simultaneously sensitize pathogenic bacteria to host defenses and pharmaceutical antibiotics.</description><subject>Amino Acid Sequence</subject><subject>antagonists & inhibitors</subject><subject>Anti-Bacterial Agents</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>antibiotic resistance</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antimicrobial Cationic Peptides</subject><subject>Antimicrobial Cationic Peptides - pharmacology</subject><subject>antimicrobial peptides</subject><subject>antimicrobial properties</subject><subject>Bacillus anthracis</subject><subject>Bacillus anthracis - drug effects</subject><subject>Bacillus anthracis - genetics</subject><subject>Bacteria</subject><subject>Bacteria - drug effects</subject><subject>Biological and medical sciences</subject><subject>Cell Membrane</subject><subject>Cell Membrane - metabolism</subject><subject>cell membranes</subject><subject>daptomycin</subject><subject>drug effects</subject><subject>Drug Resistance, Bacterial</subject><subject>Drug Synergism</subject><subject>Endopeptidase Clp</subject><subject>Endopeptidase Clp - antagonists & inhibitors</subject><subject>enzyme inhibitors</subject><subject>Escherichia coli Proteins</subject><subject>Escherichia coli Proteins - antagonists & inhibitors</subject><subject>Experimental Therapeutics</subject><subject>genetics</subject><subject>growth & development</subject><subject>Medical sciences</subject><subject>metabolism</subject><subject>Methicillin-Resistant Staphylococcus aureus</subject><subject>Methicillin-Resistant Staphylococcus aureus - drug effects</subject><subject>Molecular Sequence Data</subject><subject>pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Protease Inhibitors</subject><subject>Protease Inhibitors - pharmacology</subject><subject>protein metabolism</subject><subject>proteinases</subject><subject>Staphylococcus aureus</subject><subject>Staphylococcus aureus - drug effects</subject><subject>Staphylococcus aureus - growth & development</subject><subject>strains</subject><subject>synergism</subject><subject>Tetrazoles</subject><subject>Tetrazoles - pharmacology</subject><issn>0066-4804</issn><issn>1098-6596</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kkFvFCEUxydGY9fqzbPiwUQTpwID7HAxWSfVNmniJrWJN8IwsEPDDCOwa_p9_KAyu2vVgxfghd_7v7z3f0XxHMEzhHD9Xkp1BimqUInQg2KBIK9LRjl7WCwgZKwkNSQnxZMYb2GOKYePixOMMcU1Rovi57qXYZDKO7-xSjpwOfa2tcn6EXgDUq9B46Zva7AOPmkZdQZUmB8RfJQq6WBz0vU2Kj2lnOhsugPJgwsfE2hkzndW2c6OYDUmO1gVfDtnrGe8yyJy7ECjnQPn4047P-lypZLd6T3fWp-sik-LR0a6qJ8d79Pi5tP51-aivPry-bJZXZUy95tKziQ3jC9VpQyuJWWmZmx_Eq4romFVIU2M5h02VVt3hNSmJgbRtiVGLXF1Wnw46E7bdtCd0mMK0okp2EGGO-GlFf_-jLYXG78TWbiuOM0Cb44CwX_f6pjEYPNknJOj9tsoEGMVZYRwntF3BzRPJMagzX0ZBMVsrFitGrE3NocZf3vAZRywuPXbMOZJ_I998Xcb98K_Xc_A6yMgY_bcBDkqG_9wlHG2pDP36sD1dtP_sEGLXF3khROUCSJQTUlmXh4YI72Qm5B1bq4xRBTO6wYrXP0CCs3QAw</recordid><startdate>20120401</startdate><enddate>20120401</enddate><creator>McGillivray, Shauna M</creator><creator>Tran, Dan N</creator><creator>Ramadoss, Nitya S</creator><creator>Alumasa, John N</creator><creator>Okumura, Cheryl Y</creator><creator>Sakoulas, George</creator><creator>Vaughn, Micah M</creator><creator>Zhang, Dawn X</creator><creator>Keiler, Kenneth C</creator><creator>Nizet, Victor</creator><general>American Society for Microbiology</general><scope>FBQ</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20120401</creationdate><title>Pharmacological Inhibition of the ClpXP Protease Increases Bacterial Susceptibility to Host Cathelicidin Antimicrobial Peptides and Cell Envelope-Active Antibiotics</title><author>McGillivray, Shauna M ; Tran, Dan N ; Ramadoss, Nitya S ; Alumasa, John N ; Okumura, Cheryl Y ; Sakoulas, George ; Vaughn, Micah M ; Zhang, Dawn X ; Keiler, Kenneth C ; Nizet, Victor</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a596t-96a9f697c3cf28a56f86656f8649e34e0331e4fe9d2f3b8d448f84f15bb4fc723</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Amino Acid Sequence</topic><topic>antagonists & inhibitors</topic><topic>Anti-Bacterial Agents</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>antibiotic resistance</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antimicrobial Cationic Peptides</topic><topic>Antimicrobial Cationic Peptides - pharmacology</topic><topic>antimicrobial peptides</topic><topic>antimicrobial properties</topic><topic>Bacillus anthracis</topic><topic>Bacillus anthracis - drug effects</topic><topic>Bacillus anthracis - genetics</topic><topic>Bacteria</topic><topic>Bacteria - drug effects</topic><topic>Biological and medical sciences</topic><topic>Cell Membrane</topic><topic>Cell Membrane - metabolism</topic><topic>cell membranes</topic><topic>daptomycin</topic><topic>drug effects</topic><topic>Drug Resistance, Bacterial</topic><topic>Drug Synergism</topic><topic>Endopeptidase Clp</topic><topic>Endopeptidase Clp - antagonists & inhibitors</topic><topic>enzyme inhibitors</topic><topic>Escherichia coli Proteins</topic><topic>Escherichia coli Proteins - antagonists & inhibitors</topic><topic>Experimental Therapeutics</topic><topic>genetics</topic><topic>growth & development</topic><topic>Medical sciences</topic><topic>metabolism</topic><topic>Methicillin-Resistant Staphylococcus aureus</topic><topic>Methicillin-Resistant Staphylococcus aureus - drug effects</topic><topic>Molecular Sequence Data</topic><topic>pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Protease Inhibitors</topic><topic>Protease Inhibitors - pharmacology</topic><topic>protein metabolism</topic><topic>proteinases</topic><topic>Staphylococcus aureus</topic><topic>Staphylococcus aureus - drug effects</topic><topic>Staphylococcus aureus - growth & development</topic><topic>strains</topic><topic>synergism</topic><topic>Tetrazoles</topic><topic>Tetrazoles - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McGillivray, Shauna M</creatorcontrib><creatorcontrib>Tran, Dan N</creatorcontrib><creatorcontrib>Ramadoss, Nitya S</creatorcontrib><creatorcontrib>Alumasa, John N</creatorcontrib><creatorcontrib>Okumura, Cheryl Y</creatorcontrib><creatorcontrib>Sakoulas, George</creatorcontrib><creatorcontrib>Vaughn, Micah M</creatorcontrib><creatorcontrib>Zhang, Dawn X</creatorcontrib><creatorcontrib>Keiler, Kenneth C</creatorcontrib><creatorcontrib>Nizet, Victor</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Antimicrobial Agents and Chemotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>McGillivray, Shauna M</au><au>Tran, Dan N</au><au>Ramadoss, Nitya S</au><au>Alumasa, John N</au><au>Okumura, Cheryl Y</au><au>Sakoulas, George</au><au>Vaughn, Micah M</au><au>Zhang, Dawn X</au><au>Keiler, Kenneth C</au><au>Nizet, Victor</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacological Inhibition of the ClpXP Protease Increases Bacterial Susceptibility to Host Cathelicidin Antimicrobial Peptides and Cell Envelope-Active Antibiotics</atitle><jtitle>Antimicrobial Agents and Chemotherapy</jtitle><stitle>Antimicrob Agents Chemother</stitle><addtitle>Antimicrob Agents Chemother</addtitle><date>2012-04-01</date><risdate>2012</risdate><volume>56</volume><issue>4</issue><spage>1854</spage><epage>1861</epage><pages>1854-1861</pages><issn>0066-4804</issn><eissn>1098-6596</eissn><coden>AACHAX</coden><abstract>The ClpXP protease is a critical bacterial intracellular protease that regulates protein turnover in many bacterial species. Here we identified a pharmacological inhibitor of the ClpXP protease, F2, and evaluated its action in Bacillus anthracis and Staphylococcus aureus. We found that F2 exhibited synergistic antimicrobial activity with cathelicidin antimicrobial peptides and antibiotics that target the cell well and/or cell membrane, such as penicillin and daptomycin, in B. anthracis and drug-resistant strains of S. aureus. ClpXP inhibition represents a novel therapeutic strategy to simultaneously sensitize pathogenic bacteria to host defenses and pharmaceutical antibiotics.</abstract><cop>Washington, DC</cop><pub>American Society for Microbiology</pub><pmid>22252821</pmid><doi>10.1128/aac.05131-11</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amino Acid Sequence antagonists & inhibitors Anti-Bacterial Agents Anti-Bacterial Agents - pharmacology antibiotic resistance Antibiotics. Antiinfectious agents. Antiparasitic agents Antimicrobial Cationic Peptides Antimicrobial Cationic Peptides - pharmacology antimicrobial peptides antimicrobial properties Bacillus anthracis Bacillus anthracis - drug effects Bacillus anthracis - genetics Bacteria Bacteria - drug effects Biological and medical sciences Cell Membrane Cell Membrane - metabolism cell membranes daptomycin drug effects Drug Resistance, Bacterial Drug Synergism Endopeptidase Clp Endopeptidase Clp - antagonists & inhibitors enzyme inhibitors Escherichia coli Proteins Escherichia coli Proteins - antagonists & inhibitors Experimental Therapeutics genetics growth & development Medical sciences metabolism Methicillin-Resistant Staphylococcus aureus Methicillin-Resistant Staphylococcus aureus - drug effects Molecular Sequence Data pharmacology Pharmacology. Drug treatments Protease Inhibitors Protease Inhibitors - pharmacology protein metabolism proteinases Staphylococcus aureus Staphylococcus aureus - drug effects Staphylococcus aureus - growth & development strains synergism Tetrazoles Tetrazoles - pharmacology |
| title | Pharmacological Inhibition of the ClpXP Protease Increases Bacterial Susceptibility to Host Cathelicidin Antimicrobial Peptides and Cell Envelope-Active Antibiotics |
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