Proline Hinged Amphipathic α‑Helical Peptide Sensitizes Gram-Negative Bacteria to Various Gram-Positive Antibiotics
Gram-negative bacteria are becoming resistant to almost all currently available antibiotics. Systemically designed antimicrobial peptides (AMPs) are attractive agents to enhance the activities of antibiotics. We constructed a small Pro-scanning library using amphipathic model peptides. Measurements...
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| Veröffentlicht in: | Journal of medicinal chemistry 2020-12, Vol.63 (23), p.14937-14950 |
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| container_title | Journal of medicinal chemistry |
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| creator | Hyun, Soonsil Choi, Yoonhwa Jo, Doyeon Choo, Seolah Park, Tae Woo Park, Su-Jin Kim, Seoyeon Lee, Seonju Park, Sohyun Jin, Sun Mi Cheon, Dae Hee Yoo, Wanki Arya, Rekha Chong, Yong Pil Kim, Kyeong Kyu Kim, Yang Soo Lee, Yan Yu, Jaehoon |
| description | Gram-negative bacteria are becoming resistant to almost all currently available antibiotics. Systemically designed antimicrobial peptides (AMPs) are attractive agents to enhance the activities of antibiotics. We constructed a small Pro-scanning library using amphipathic model peptides. Measurements of minimum inhibitory concentration (MIC) against Escherichia coli and hemolytic activities showed that one of the Pro-hinged peptides, KL-L9P, displays the highest specificity toward E. coli. Moreover, KL-L9P sensitizes E. coli to be responsive to most antibiotics that are not active against Gram-negative bacteria. The results of biochemical experiments show that KL-L9P promotes the rearrangement of the bacterial membrane that enables hydrophobic antibiotics to permeate. Finally, the results of animal tests demonstrate that KL-L9P strongly sensitizes Gram-negative bacteria to linezolid (Lzd), rifampicin (Rif), or clarithromycin (Clr). Thus, KL-L9P operates as a sensitizer to extend the antibacterial activity of most antibiotics to Gram-negative bacteria. |
| doi_str_mv | 10.1021/acs.jmedchem.0c01506 |
| format | Article |
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Systemically designed antimicrobial peptides (AMPs) are attractive agents to enhance the activities of antibiotics. We constructed a small Pro-scanning library using amphipathic model peptides. Measurements of minimum inhibitory concentration (MIC) against Escherichia coli and hemolytic activities showed that one of the Pro-hinged peptides, KL-L9P, displays the highest specificity toward E. coli. Moreover, KL-L9P sensitizes E. coli to be responsive to most antibiotics that are not active against Gram-negative bacteria. The results of biochemical experiments show that KL-L9P promotes the rearrangement of the bacterial membrane that enables hydrophobic antibiotics to permeate. Finally, the results of animal tests demonstrate that KL-L9P strongly sensitizes Gram-negative bacteria to linezolid (Lzd), rifampicin (Rif), or clarithromycin (Clr). Thus, KL-L9P operates as a sensitizer to extend the antibacterial activity of most antibiotics to Gram-negative bacteria.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.0c01506</identifier><identifier>PMID: 33205989</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Anti-Bacterial Agents - chemistry ; Anti-Bacterial Agents - pharmacology ; Antimicrobial Cationic Peptides - chemistry ; Antimicrobial Cationic Peptides - metabolism ; Antimicrobial Cationic Peptides - pharmacology ; Cell Membrane - drug effects ; Clarithromycin - pharmacology ; Escherichia coli - drug effects ; Female ; Hemolysis - drug effects ; Humans ; Hydrophobic and Hydrophilic Interactions ; Linezolid - pharmacology ; Lipid A - metabolism ; Membrane Fluidity - drug effects ; Mice, Inbred ICR ; Microbial Sensitivity Tests ; Proline - chemistry ; Protein Binding ; Protein Conformation, alpha-Helical ; Rifampin - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2020-12, Vol.63 (23), p.14937-14950</ispartof><rights>2020 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-e345f4e9c8cfd5683f293430f868db9270eb178d000dba9276ccbb828fcf50d23</citedby><cites>FETCH-LOGICAL-a348t-e345f4e9c8cfd5683f293430f868db9270eb178d000dba9276ccbb828fcf50d23</cites><orcidid>0000-0003-2515-8894 ; 0000-0003-4222-4398 ; 0000-0002-3400-7353 ; 0000-0003-2498-1301</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.0c01506$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01506$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33205989$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hyun, Soonsil</creatorcontrib><creatorcontrib>Choi, Yoonhwa</creatorcontrib><creatorcontrib>Jo, Doyeon</creatorcontrib><creatorcontrib>Choo, Seolah</creatorcontrib><creatorcontrib>Park, Tae Woo</creatorcontrib><creatorcontrib>Park, Su-Jin</creatorcontrib><creatorcontrib>Kim, Seoyeon</creatorcontrib><creatorcontrib>Lee, Seonju</creatorcontrib><creatorcontrib>Park, Sohyun</creatorcontrib><creatorcontrib>Jin, Sun Mi</creatorcontrib><creatorcontrib>Cheon, Dae Hee</creatorcontrib><creatorcontrib>Yoo, Wanki</creatorcontrib><creatorcontrib>Arya, Rekha</creatorcontrib><creatorcontrib>Chong, Yong Pil</creatorcontrib><creatorcontrib>Kim, Kyeong Kyu</creatorcontrib><creatorcontrib>Kim, Yang Soo</creatorcontrib><creatorcontrib>Lee, Yan</creatorcontrib><creatorcontrib>Yu, Jaehoon</creatorcontrib><title>Proline Hinged Amphipathic α‑Helical Peptide Sensitizes Gram-Negative Bacteria to Various Gram-Positive Antibiotics</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Gram-negative bacteria are becoming resistant to almost all currently available antibiotics. Systemically designed antimicrobial peptides (AMPs) are attractive agents to enhance the activities of antibiotics. We constructed a small Pro-scanning library using amphipathic model peptides. Measurements of minimum inhibitory concentration (MIC) against Escherichia coli and hemolytic activities showed that one of the Pro-hinged peptides, KL-L9P, displays the highest specificity toward E. coli. Moreover, KL-L9P sensitizes E. coli to be responsive to most antibiotics that are not active against Gram-negative bacteria. The results of biochemical experiments show that KL-L9P promotes the rearrangement of the bacterial membrane that enables hydrophobic antibiotics to permeate. Finally, the results of animal tests demonstrate that KL-L9P strongly sensitizes Gram-negative bacteria to linezolid (Lzd), rifampicin (Rif), or clarithromycin (Clr). 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Choi, Yoonhwa ; Jo, Doyeon ; Choo, Seolah ; Park, Tae Woo ; Park, Su-Jin ; Kim, Seoyeon ; Lee, Seonju ; Park, Sohyun ; Jin, Sun Mi ; Cheon, Dae Hee ; Yoo, Wanki ; Arya, Rekha ; Chong, Yong Pil ; Kim, Kyeong Kyu ; Kim, Yang Soo ; Lee, Yan ; Yu, Jaehoon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-e345f4e9c8cfd5683f293430f868db9270eb178d000dba9276ccbb828fcf50d23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Anti-Bacterial Agents - chemistry</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Antimicrobial Cationic Peptides - chemistry</topic><topic>Antimicrobial Cationic Peptides - metabolism</topic><topic>Antimicrobial Cationic Peptides - pharmacology</topic><topic>Cell Membrane - drug effects</topic><topic>Clarithromycin - pharmacology</topic><topic>Escherichia coli - drug effects</topic><topic>Female</topic><topic>Hemolysis - drug effects</topic><topic>Humans</topic><topic>Hydrophobic and Hydrophilic Interactions</topic><topic>Linezolid - pharmacology</topic><topic>Lipid A - metabolism</topic><topic>Membrane Fluidity - drug effects</topic><topic>Mice, Inbred ICR</topic><topic>Microbial Sensitivity Tests</topic><topic>Proline - chemistry</topic><topic>Protein Binding</topic><topic>Protein Conformation, alpha-Helical</topic><topic>Rifampin - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hyun, Soonsil</creatorcontrib><creatorcontrib>Choi, Yoonhwa</creatorcontrib><creatorcontrib>Jo, Doyeon</creatorcontrib><creatorcontrib>Choo, Seolah</creatorcontrib><creatorcontrib>Park, Tae Woo</creatorcontrib><creatorcontrib>Park, Su-Jin</creatorcontrib><creatorcontrib>Kim, Seoyeon</creatorcontrib><creatorcontrib>Lee, Seonju</creatorcontrib><creatorcontrib>Park, Sohyun</creatorcontrib><creatorcontrib>Jin, Sun Mi</creatorcontrib><creatorcontrib>Cheon, Dae Hee</creatorcontrib><creatorcontrib>Yoo, Wanki</creatorcontrib><creatorcontrib>Arya, Rekha</creatorcontrib><creatorcontrib>Chong, Yong Pil</creatorcontrib><creatorcontrib>Kim, Kyeong Kyu</creatorcontrib><creatorcontrib>Kim, Yang Soo</creatorcontrib><creatorcontrib>Lee, Yan</creatorcontrib><creatorcontrib>Yu, Jaehoon</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hyun, Soonsil</au><au>Choi, Yoonhwa</au><au>Jo, Doyeon</au><au>Choo, Seolah</au><au>Park, Tae Woo</au><au>Park, Su-Jin</au><au>Kim, Seoyeon</au><au>Lee, Seonju</au><au>Park, Sohyun</au><au>Jin, Sun Mi</au><au>Cheon, Dae Hee</au><au>Yoo, Wanki</au><au>Arya, Rekha</au><au>Chong, Yong Pil</au><au>Kim, Kyeong Kyu</au><au>Kim, Yang Soo</au><au>Lee, Yan</au><au>Yu, Jaehoon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Proline Hinged Amphipathic α‑Helical Peptide Sensitizes Gram-Negative Bacteria to Various Gram-Positive Antibiotics</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2020-12-10</date><risdate>2020</risdate><volume>63</volume><issue>23</issue><spage>14937</spage><epage>14950</epage><pages>14937-14950</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Gram-negative bacteria are becoming resistant to almost all currently available antibiotics. Systemically designed antimicrobial peptides (AMPs) are attractive agents to enhance the activities of antibiotics. We constructed a small Pro-scanning library using amphipathic model peptides. Measurements of minimum inhibitory concentration (MIC) against Escherichia coli and hemolytic activities showed that one of the Pro-hinged peptides, KL-L9P, displays the highest specificity toward E. coli. Moreover, KL-L9P sensitizes E. coli to be responsive to most antibiotics that are not active against Gram-negative bacteria. The results of biochemical experiments show that KL-L9P promotes the rearrangement of the bacterial membrane that enables hydrophobic antibiotics to permeate. Finally, the results of animal tests demonstrate that KL-L9P strongly sensitizes Gram-negative bacteria to linezolid (Lzd), rifampicin (Rif), or clarithromycin (Clr). Thus, KL-L9P operates as a sensitizer to extend the antibacterial activity of most antibiotics to Gram-negative bacteria.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>33205989</pmid><doi>10.1021/acs.jmedchem.0c01506</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-2515-8894</orcidid><orcidid>https://orcid.org/0000-0003-4222-4398</orcidid><orcidid>https://orcid.org/0000-0002-3400-7353</orcidid><orcidid>https://orcid.org/0000-0003-2498-1301</orcidid></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2020-12, Vol.63 (23), p.14937-14950 |
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| source | MEDLINE; ACS Publications |
| subjects | Animals Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Antimicrobial Cationic Peptides - chemistry Antimicrobial Cationic Peptides - metabolism Antimicrobial Cationic Peptides - pharmacology Cell Membrane - drug effects Clarithromycin - pharmacology Escherichia coli - drug effects Female Hemolysis - drug effects Humans Hydrophobic and Hydrophilic Interactions Linezolid - pharmacology Lipid A - metabolism Membrane Fluidity - drug effects Mice, Inbred ICR Microbial Sensitivity Tests Proline - chemistry Protein Binding Protein Conformation, alpha-Helical Rifampin - pharmacology |
| title | Proline Hinged Amphipathic α‑Helical Peptide Sensitizes Gram-Negative Bacteria to Various Gram-Positive Antibiotics |
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