Leucyl-tRNA Synthetase Inhibitor, D-Norvaline, in Combination with Oxacillin, Is Effective against Methicillin-Resistant <i>Staphylococcus aureus</i>
Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) is a pathogenic bacterium that causes severe diseases in humans. For decades, MRSA has acquired substantial resistance against conventional antibiotics through regulatory adaptation, thereby posing a challenge for treating MRSA in...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-05-01
|
| Series: | Antibiotics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-6382/11/5/683 |
| _version_ | 1797502024923742208 |
|---|---|
| author | Hong-Ju Lee Byungchan Kim Suhyun Kim Do-Hyun Cho Heeju Jung Wooseong Kim Yun-Gon Kim Jae-Seok Kim Hwang-Soo Joo Sang-Ho Lee Yung-Hun Yang |
| author_facet | Hong-Ju Lee Byungchan Kim Suhyun Kim Do-Hyun Cho Heeju Jung Wooseong Kim Yun-Gon Kim Jae-Seok Kim Hwang-Soo Joo Sang-Ho Lee Yung-Hun Yang |
| author_sort | Hong-Ju Lee |
| collection | DOAJ |
| description | Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) is a pathogenic bacterium that causes severe diseases in humans. For decades, MRSA has acquired substantial resistance against conventional antibiotics through regulatory adaptation, thereby posing a challenge for treating MRSA infection. One of the emerging strategies to combat MRSA is the combinatory use of antibacterial agents. Based on the dramatic change in phospholipid fatty acid (PLFA) composition of MRSA in previous results, this study investigated branched-chain amino acid derivatives (precursors of fatty acid synthesis of cell membrane) and discovered the antimicrobial potency of D-norvaline. The compound, which can act synergistically with oxacillin, is among the three leucine-tRNA synthetase inhibitors with high potency to inhibit MRSA cell growth and biofilm formation. PLFA analysis and membrane properties revealed that D-norvaline decreased the overall amount of PLFA, increasing the fluidity and decreasing the hydrophobicity of the bacterial cell membrane. Additionally, we observed genetic differences to explore the response to D-norvaline. Furthermore, deletion mutants and clinically isolated MRSA strains were treated with D-norvaline. The study revealed that D-norvaline, with low concentrations of oxacillin, was effective in killing several MRSA strains. In summary, our findings provide a new combination of aminoacyl-tRNA synthetase inhibitor D-norvaline and oxacillin, which is effective against MRSA. |
| first_indexed | 2024-03-10T03:27:02Z |
| format | Article |
| id | doaj.art-19621a5bd7fc435386fbb4ed1d3b5b31 |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-10T03:27:02Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-19621a5bd7fc435386fbb4ed1d3b5b312023-11-23T09:49:38ZengMDPI AGAntibiotics2079-63822022-05-0111568310.3390/antibiotics11050683Leucyl-tRNA Synthetase Inhibitor, D-Norvaline, in Combination with Oxacillin, Is Effective against Methicillin-Resistant <i>Staphylococcus aureus</i>Hong-Ju Lee0Byungchan Kim1Suhyun Kim2Do-Hyun Cho3Heeju Jung4Wooseong Kim5Yun-Gon Kim6Jae-Seok Kim7Hwang-Soo Joo8Sang-Ho Lee9Yung-Hun Yang10Department of Biological Engineering, College of Engineering, Konkuk University, Seoul 05029, KoreaDepartment of Biological Engineering, College of Engineering, Konkuk University, Seoul 05029, KoreaDepartment of Biological Engineering, College of Engineering, Konkuk University, Seoul 05029, KoreaDepartment of Biological Engineering, College of Engineering, Konkuk University, Seoul 05029, KoreaDepartment of Biological Engineering, College of Engineering, Konkuk University, Seoul 05029, KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, KoreaDepartment of Chemical Engineering, Soongsil University, Seoul 06978, KoreaDepartment of Laboratory Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul 05355, KoreaDepartment of Biotechnology, College of Engineering, Duksung Women’s University, Seoul 01369, KoreaDepartment of Pharmacy, College of Pharmacy, Jeju National University, Jeju-si 63243, KoreaDepartment of Biological Engineering, College of Engineering, Konkuk University, Seoul 05029, KoreaMethicillin-resistant <i>Staphylococcus aureus</i> (MRSA) is a pathogenic bacterium that causes severe diseases in humans. For decades, MRSA has acquired substantial resistance against conventional antibiotics through regulatory adaptation, thereby posing a challenge for treating MRSA infection. One of the emerging strategies to combat MRSA is the combinatory use of antibacterial agents. Based on the dramatic change in phospholipid fatty acid (PLFA) composition of MRSA in previous results, this study investigated branched-chain amino acid derivatives (precursors of fatty acid synthesis of cell membrane) and discovered the antimicrobial potency of D-norvaline. The compound, which can act synergistically with oxacillin, is among the three leucine-tRNA synthetase inhibitors with high potency to inhibit MRSA cell growth and biofilm formation. PLFA analysis and membrane properties revealed that D-norvaline decreased the overall amount of PLFA, increasing the fluidity and decreasing the hydrophobicity of the bacterial cell membrane. Additionally, we observed genetic differences to explore the response to D-norvaline. Furthermore, deletion mutants and clinically isolated MRSA strains were treated with D-norvaline. The study revealed that D-norvaline, with low concentrations of oxacillin, was effective in killing several MRSA strains. In summary, our findings provide a new combination of aminoacyl-tRNA synthetase inhibitor D-norvaline and oxacillin, which is effective against MRSA.https://www.mdpi.com/2079-6382/11/5/683MRSAD-norvalineaminoacyl-tRNA synthetase inhibitordrug combination therapy |
| spellingShingle | Hong-Ju Lee Byungchan Kim Suhyun Kim Do-Hyun Cho Heeju Jung Wooseong Kim Yun-Gon Kim Jae-Seok Kim Hwang-Soo Joo Sang-Ho Lee Yung-Hun Yang Leucyl-tRNA Synthetase Inhibitor, D-Norvaline, in Combination with Oxacillin, Is Effective against Methicillin-Resistant <i>Staphylococcus aureus</i> Antibiotics MRSA D-norvaline aminoacyl-tRNA synthetase inhibitor drug combination therapy |
| title | Leucyl-tRNA Synthetase Inhibitor, D-Norvaline, in Combination with Oxacillin, Is Effective against Methicillin-Resistant <i>Staphylococcus aureus</i> |
| title_full | Leucyl-tRNA Synthetase Inhibitor, D-Norvaline, in Combination with Oxacillin, Is Effective against Methicillin-Resistant <i>Staphylococcus aureus</i> |
| title_fullStr | Leucyl-tRNA Synthetase Inhibitor, D-Norvaline, in Combination with Oxacillin, Is Effective against Methicillin-Resistant <i>Staphylococcus aureus</i> |
| title_full_unstemmed | Leucyl-tRNA Synthetase Inhibitor, D-Norvaline, in Combination with Oxacillin, Is Effective against Methicillin-Resistant <i>Staphylococcus aureus</i> |
| title_short | Leucyl-tRNA Synthetase Inhibitor, D-Norvaline, in Combination with Oxacillin, Is Effective against Methicillin-Resistant <i>Staphylococcus aureus</i> |
| title_sort | leucyl trna synthetase inhibitor d norvaline in combination with oxacillin is effective against methicillin resistant i staphylococcus aureus i |
| topic | MRSA D-norvaline aminoacyl-tRNA synthetase inhibitor drug combination therapy |
| url | https://www.mdpi.com/2079-6382/11/5/683 |
| work_keys_str_mv | AT hongjulee leucyltrnasynthetaseinhibitordnorvalineincombinationwithoxacilliniseffectiveagainstmethicillinresistantistaphylococcusaureusi AT byungchankim leucyltrnasynthetaseinhibitordnorvalineincombinationwithoxacilliniseffectiveagainstmethicillinresistantistaphylococcusaureusi AT suhyunkim leucyltrnasynthetaseinhibitordnorvalineincombinationwithoxacilliniseffectiveagainstmethicillinresistantistaphylococcusaureusi AT dohyuncho leucyltrnasynthetaseinhibitordnorvalineincombinationwithoxacilliniseffectiveagainstmethicillinresistantistaphylococcusaureusi AT heejujung leucyltrnasynthetaseinhibitordnorvalineincombinationwithoxacilliniseffectiveagainstmethicillinresistantistaphylococcusaureusi AT wooseongkim leucyltrnasynthetaseinhibitordnorvalineincombinationwithoxacilliniseffectiveagainstmethicillinresistantistaphylococcusaureusi AT yungonkim leucyltrnasynthetaseinhibitordnorvalineincombinationwithoxacilliniseffectiveagainstmethicillinresistantistaphylococcusaureusi AT jaeseokkim leucyltrnasynthetaseinhibitordnorvalineincombinationwithoxacilliniseffectiveagainstmethicillinresistantistaphylococcusaureusi AT hwangsoojoo leucyltrnasynthetaseinhibitordnorvalineincombinationwithoxacilliniseffectiveagainstmethicillinresistantistaphylococcusaureusi AT sangholee leucyltrnasynthetaseinhibitordnorvalineincombinationwithoxacilliniseffectiveagainstmethicillinresistantistaphylococcusaureusi AT yunghunyang leucyltrnasynthetaseinhibitordnorvalineincombinationwithoxacilliniseffectiveagainstmethicillinresistantistaphylococcusaureusi |