Discovery of Quinazolone Pyridiniums as Potential Broad-Spectrum Antibacterial Agents
The overprescription of antibiotics in medicine and agriculture has accelerated the development and spread of antibiotic resistance in bacteria, which severely limits the arsenal available to clinicians for treating bacterial infections. This work discovered a new class of heteroarylcyanovinyl quina...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/2/243 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832587875660595200 |
|---|---|
| author | Jie Dai Qianyue Li Ziyi Li Zhonglin Zang Yan Luo Chenghe Zhou |
| author_facet | Jie Dai Qianyue Li Ziyi Li Zhonglin Zang Yan Luo Chenghe Zhou |
| author_sort | Jie Dai |
| collection | DOAJ |
| description | The overprescription of antibiotics in medicine and agriculture has accelerated the development and spread of antibiotic resistance in bacteria, which severely limits the arsenal available to clinicians for treating bacterial infections. This work discovered a new class of heteroarylcyanovinyl quinazolones and quinazolone pyridiniums to surmount the increasingly severe bacterial resistance. Bioactive assays manifested that the highly active compound <b>19a</b> exhibited strong inhibition against MRSA and <i>Escherichia coli</i> with extremely low MICs of 0.5 μg/mL, being eightfold more active than that of norfloxacin (MICs = 4 μg/mL). The highly active <b>19a</b> with rapid bactericidal properties displayed imperceptible resistance development trends, negligible hemolytic toxicity, and effective biofilm inhibitory effects. Preliminary explorations on antibacterial mechanisms revealed that compound <b>19a</b> could cause membrane damage, embed in intracellular DNA to hinder bacterial DNA replication, and induce metabolic dysfunction. Surprisingly, active <b>19a</b> was found to trigger the conformational change in PBP2a of MRSA to open the active site, which might account for its high inhibition against MRSA. In addition, the little effect of molecule <b>19a</b> on the production of reactive oxygen species indicated that bacterial death was not caused by oxidative stress. The above comprehensive analyses highlighted the large potential of quinazolone pyridiniums as multitargeting broad-spectrum antibacterial agents. |
| format | Article |
| id | doaj-art-b57c38c8f7a84eaca7ccc747fc220b8b |
| institution | Kabale University |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-b57c38c8f7a84eaca7ccc747fc220b8b2025-01-24T13:43:14ZengMDPI AGMolecules1420-30492025-01-0130224310.3390/molecules30020243Discovery of Quinazolone Pyridiniums as Potential Broad-Spectrum Antibacterial AgentsJie Dai0Qianyue Li1Ziyi Li2Zhonglin Zang3Yan Luo4Chenghe Zhou5Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, ChinaInstitute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, ChinaInstitute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, ChinaInstitute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, ChinaCollege of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing 402160, ChinaInstitute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, ChinaThe overprescription of antibiotics in medicine and agriculture has accelerated the development and spread of antibiotic resistance in bacteria, which severely limits the arsenal available to clinicians for treating bacterial infections. This work discovered a new class of heteroarylcyanovinyl quinazolones and quinazolone pyridiniums to surmount the increasingly severe bacterial resistance. Bioactive assays manifested that the highly active compound <b>19a</b> exhibited strong inhibition against MRSA and <i>Escherichia coli</i> with extremely low MICs of 0.5 μg/mL, being eightfold more active than that of norfloxacin (MICs = 4 μg/mL). The highly active <b>19a</b> with rapid bactericidal properties displayed imperceptible resistance development trends, negligible hemolytic toxicity, and effective biofilm inhibitory effects. Preliminary explorations on antibacterial mechanisms revealed that compound <b>19a</b> could cause membrane damage, embed in intracellular DNA to hinder bacterial DNA replication, and induce metabolic dysfunction. Surprisingly, active <b>19a</b> was found to trigger the conformational change in PBP2a of MRSA to open the active site, which might account for its high inhibition against MRSA. In addition, the little effect of molecule <b>19a</b> on the production of reactive oxygen species indicated that bacterial death was not caused by oxidative stress. The above comprehensive analyses highlighted the large potential of quinazolone pyridiniums as multitargeting broad-spectrum antibacterial agents.https://www.mdpi.com/1420-3049/30/2/243quinazolonepyridiniumresistanceantibacterialPBP2a |
| spellingShingle | Jie Dai Qianyue Li Ziyi Li Zhonglin Zang Yan Luo Chenghe Zhou Discovery of Quinazolone Pyridiniums as Potential Broad-Spectrum Antibacterial Agents Molecules quinazolone pyridinium resistance antibacterial PBP2a |
| title | Discovery of Quinazolone Pyridiniums as Potential Broad-Spectrum Antibacterial Agents |
| title_full | Discovery of Quinazolone Pyridiniums as Potential Broad-Spectrum Antibacterial Agents |
| title_fullStr | Discovery of Quinazolone Pyridiniums as Potential Broad-Spectrum Antibacterial Agents |
| title_full_unstemmed | Discovery of Quinazolone Pyridiniums as Potential Broad-Spectrum Antibacterial Agents |
| title_short | Discovery of Quinazolone Pyridiniums as Potential Broad-Spectrum Antibacterial Agents |
| title_sort | discovery of quinazolone pyridiniums as potential broad spectrum antibacterial agents |
| topic | quinazolone pyridinium resistance antibacterial PBP2a |
| url | https://www.mdpi.com/1420-3049/30/2/243 |
| work_keys_str_mv | AT jiedai discoveryofquinazolonepyridiniumsaspotentialbroadspectrumantibacterialagents AT qianyueli discoveryofquinazolonepyridiniumsaspotentialbroadspectrumantibacterialagents AT ziyili discoveryofquinazolonepyridiniumsaspotentialbroadspectrumantibacterialagents AT zhonglinzang discoveryofquinazolonepyridiniumsaspotentialbroadspectrumantibacterialagents AT yanluo discoveryofquinazolonepyridiniumsaspotentialbroadspectrumantibacterialagents AT chenghezhou discoveryofquinazolonepyridiniumsaspotentialbroadspectrumantibacterialagents |