Isoquinoline Antimicrobial Agent: Activity against Intracellular Bacteria and Effect on Global Bacterial Proteome
A new class of alkynyl isoquinoline antibacterial compounds, synthesized via Sonogashira coupling, with strong bactericidal activity against a plethora of Gram-positive bacteria including methicillin- and vancomycin-resistant <i>Staphylococcus aureus (S. aureus)</i> strains is presented....
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-08-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/27/16/5085 |
| _version_ | 1797443179806457856 |
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| author | Caroline W. Karanja Nimishetti Naganna Nader S. Abutaleb Neetu Dayal Kenneth I. Onyedibe Uma Aryal Mohamed N. Seleem Herman O. Sintim |
| author_facet | Caroline W. Karanja Nimishetti Naganna Nader S. Abutaleb Neetu Dayal Kenneth I. Onyedibe Uma Aryal Mohamed N. Seleem Herman O. Sintim |
| author_sort | Caroline W. Karanja |
| collection | DOAJ |
| description | A new class of alkynyl isoquinoline antibacterial compounds, synthesized via Sonogashira coupling, with strong bactericidal activity against a plethora of Gram-positive bacteria including methicillin- and vancomycin-resistant <i>Staphylococcus aureus (S. aureus)</i> strains is presented. HSN584 and HSN739, representative compounds in this class, reduce methicillin-resistant <i>S. aureus</i> (MRSA) load in macrophages, whilst vancomycin, a drug of choice for MRSA infections, was unable to clear intracellular MRSA. Additionally, both HSN584 and HSN739 exhibited a low propensity to develop resistance. We utilized comparative global proteomics and macromolecule biosynthesis assays to gain insight into the alkynyl isoquinoline mechanism of action. Our preliminary data show that HSN584 perturb <i>S. aureus</i> cell wall and nucleic acid biosynthesis. The alkynyl isoquinoline moiety is a new scaffold for the development of potent antibacterial agents against fatal multidrug-resistant Gram-positive bacteria. |
| first_indexed | 2024-03-09T12:53:16Z |
| format | Article |
| id | doaj.art-c6e05fb522464e4eb21a3521ac1bfb0e |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T12:53:16Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-c6e05fb522464e4eb21a3521ac1bfb0e2023-11-30T22:04:06ZengMDPI AGMolecules1420-30492022-08-012716508510.3390/molecules27165085Isoquinoline Antimicrobial Agent: Activity against Intracellular Bacteria and Effect on Global Bacterial ProteomeCaroline W. Karanja0Nimishetti Naganna1Nader S. Abutaleb2Neetu Dayal3Kenneth I. Onyedibe4Uma Aryal5Mohamed N. Seleem6Herman O. Sintim7Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USADepartment of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USADepartment of Comparative Pathobiology, Purdue University College of Veterinary Medicine, 625 Harrison Street, West Lafayette, IN 47907, USADepartment of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USADepartment of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USADepartment of Comparative Pathobiology, Purdue University College of Veterinary Medicine, 625 Harrison Street, West Lafayette, IN 47907, USADepartment of Comparative Pathobiology, Purdue University College of Veterinary Medicine, 625 Harrison Street, West Lafayette, IN 47907, USADepartment of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USAA new class of alkynyl isoquinoline antibacterial compounds, synthesized via Sonogashira coupling, with strong bactericidal activity against a plethora of Gram-positive bacteria including methicillin- and vancomycin-resistant <i>Staphylococcus aureus (S. aureus)</i> strains is presented. HSN584 and HSN739, representative compounds in this class, reduce methicillin-resistant <i>S. aureus</i> (MRSA) load in macrophages, whilst vancomycin, a drug of choice for MRSA infections, was unable to clear intracellular MRSA. Additionally, both HSN584 and HSN739 exhibited a low propensity to develop resistance. We utilized comparative global proteomics and macromolecule biosynthesis assays to gain insight into the alkynyl isoquinoline mechanism of action. Our preliminary data show that HSN584 perturb <i>S. aureus</i> cell wall and nucleic acid biosynthesis. The alkynyl isoquinoline moiety is a new scaffold for the development of potent antibacterial agents against fatal multidrug-resistant Gram-positive bacteria.https://www.mdpi.com/1420-3049/27/16/5085antimicrobial resistanceallkynyl isoquinoliesSonogashira couplingintracellular clearance |
| spellingShingle | Caroline W. Karanja Nimishetti Naganna Nader S. Abutaleb Neetu Dayal Kenneth I. Onyedibe Uma Aryal Mohamed N. Seleem Herman O. Sintim Isoquinoline Antimicrobial Agent: Activity against Intracellular Bacteria and Effect on Global Bacterial Proteome Molecules antimicrobial resistance allkynyl isoquinolies Sonogashira coupling intracellular clearance |
| title | Isoquinoline Antimicrobial Agent: Activity against Intracellular Bacteria and Effect on Global Bacterial Proteome |
| title_full | Isoquinoline Antimicrobial Agent: Activity against Intracellular Bacteria and Effect on Global Bacterial Proteome |
| title_fullStr | Isoquinoline Antimicrobial Agent: Activity against Intracellular Bacteria and Effect on Global Bacterial Proteome |
| title_full_unstemmed | Isoquinoline Antimicrobial Agent: Activity against Intracellular Bacteria and Effect on Global Bacterial Proteome |
| title_short | Isoquinoline Antimicrobial Agent: Activity against Intracellular Bacteria and Effect on Global Bacterial Proteome |
| title_sort | isoquinoline antimicrobial agent activity against intracellular bacteria and effect on global bacterial proteome |
| topic | antimicrobial resistance allkynyl isoquinolies Sonogashira coupling intracellular clearance |
| url | https://www.mdpi.com/1420-3049/27/16/5085 |
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