Galactose-Clicked Curcumin-Mediated Reversal of Meropenem Resistance among <i>Klebsiella pneumoniae</i> by Targeting Its Carbapenemases and the AcrAB-TolC Efflux System
In over eighty years, despite successive antibiotics discoveries, the rapid advent of multidrug resistance among bacterial pathogens has jolted our misapprehension of success over them. Resistance is spreading faster than the discovery of new antibiotics/antimicrobials. Therefore, the search for bet...
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MDPI AG
2021-04-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/10/4/388 |
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| author | Shivangi Yadav Ashish Kumar Singh Anand K. Agrahari Akhilesh Kumar Pandey Munesh Kumar Gupta Dipshikha Chakravortty Vinod Kumar Tiwari Pradyot Prakash |
| author_facet | Shivangi Yadav Ashish Kumar Singh Anand K. Agrahari Akhilesh Kumar Pandey Munesh Kumar Gupta Dipshikha Chakravortty Vinod Kumar Tiwari Pradyot Prakash |
| author_sort | Shivangi Yadav |
| collection | DOAJ |
| description | In over eighty years, despite successive antibiotics discoveries, the rapid advent of multidrug resistance among bacterial pathogens has jolted our misapprehension of success over them. Resistance is spreading faster than the discovery of new antibiotics/antimicrobials. Therefore, the search for better antimicrobials/additives becomes prudent. A water-soluble curcumin derivative (Cur<sub>aq</sub>) was synthesised, employing a Cu (I) catalysed 1, 3-cyclo addition reaction; it has been evaluated as a potential treatment for multidrug-resistant isolates and as an antibiotic adjuvant for meropenem against hypervirulent multidrug-resistant <i>Klebsiella pneumoniae</i> isolates. We also investigated its solubility and effect over carbapenemase activity. Additionally, we investigated its impact on the AcrAB-TolC system. We found that Cur<sub>aq</sub> inhibited bacterial growth at a minimal concentration of 16 µg/mL; at a 32 µg/mL concentration, it killed bacterial growth completely. Only nine (9.4%) <i>Klebsiella</i> isolates were sensitive to meropenem; however, after synergising with Cur<sub>aq</sub> (8 µg/mL), 85 (88.54%) hvKP isolates became sensitive to the drug. The Cur<sub>aq</sub> also inhibited the AcrAB-TolC efflux system at 1 µg/mL concentration by disrupting the membrane potential and causing depolarisation. The kinetic parameters obtained also indicated its promise as a carbapenemase inhibitor. These results suggest that Cur<sub>aq</sub> can be an excellent drug candidate as a broad-spectrum antibacterial and anti-efflux agent. |
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| language | English |
| last_indexed | 2024-03-10T12:37:05Z |
| publishDate | 2021-04-01 |
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| series | Antibiotics |
| spelling | doaj.art-cb0574a945ed4244950f8c9f0a50f2d82023-11-21T14:13:06ZengMDPI AGAntibiotics2079-63822021-04-0110438810.3390/antibiotics10040388Galactose-Clicked Curcumin-Mediated Reversal of Meropenem Resistance among <i>Klebsiella pneumoniae</i> by Targeting Its Carbapenemases and the AcrAB-TolC Efflux SystemShivangi Yadav0Ashish Kumar Singh1Anand K. Agrahari2Akhilesh Kumar Pandey3Munesh Kumar Gupta4Dipshikha Chakravortty5Vinod Kumar Tiwari6Pradyot Prakash7Bacterial Biofilm and Drug Resistance Research Laboratory, Department of Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, IndiaBacterial Biofilm and Drug Resistance Research Laboratory, Department of Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, IndiaDepartment of Chemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, IndiaDepartment of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, IndiaBacterial Biofilm and Drug Resistance Research Laboratory, Department of Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, IndiaDepartment of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560012, IndiaDepartment of Chemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, IndiaBacterial Biofilm and Drug Resistance Research Laboratory, Department of Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, IndiaIn over eighty years, despite successive antibiotics discoveries, the rapid advent of multidrug resistance among bacterial pathogens has jolted our misapprehension of success over them. Resistance is spreading faster than the discovery of new antibiotics/antimicrobials. Therefore, the search for better antimicrobials/additives becomes prudent. A water-soluble curcumin derivative (Cur<sub>aq</sub>) was synthesised, employing a Cu (I) catalysed 1, 3-cyclo addition reaction; it has been evaluated as a potential treatment for multidrug-resistant isolates and as an antibiotic adjuvant for meropenem against hypervirulent multidrug-resistant <i>Klebsiella pneumoniae</i> isolates. We also investigated its solubility and effect over carbapenemase activity. Additionally, we investigated its impact on the AcrAB-TolC system. We found that Cur<sub>aq</sub> inhibited bacterial growth at a minimal concentration of 16 µg/mL; at a 32 µg/mL concentration, it killed bacterial growth completely. Only nine (9.4%) <i>Klebsiella</i> isolates were sensitive to meropenem; however, after synergising with Cur<sub>aq</sub> (8 µg/mL), 85 (88.54%) hvKP isolates became sensitive to the drug. The Cur<sub>aq</sub> also inhibited the AcrAB-TolC efflux system at 1 µg/mL concentration by disrupting the membrane potential and causing depolarisation. The kinetic parameters obtained also indicated its promise as a carbapenemase inhibitor. These results suggest that Cur<sub>aq</sub> can be an excellent drug candidate as a broad-spectrum antibacterial and anti-efflux agent.https://www.mdpi.com/2079-6382/10/4/388bliss modellingsynergismAcrAB-TolCbla_KPCmCIMeCIM |
| spellingShingle | Shivangi Yadav Ashish Kumar Singh Anand K. Agrahari Akhilesh Kumar Pandey Munesh Kumar Gupta Dipshikha Chakravortty Vinod Kumar Tiwari Pradyot Prakash Galactose-Clicked Curcumin-Mediated Reversal of Meropenem Resistance among <i>Klebsiella pneumoniae</i> by Targeting Its Carbapenemases and the AcrAB-TolC Efflux System Antibiotics bliss modelling synergism AcrAB-TolC bla_KPC mCIM eCIM |
| title | Galactose-Clicked Curcumin-Mediated Reversal of Meropenem Resistance among <i>Klebsiella pneumoniae</i> by Targeting Its Carbapenemases and the AcrAB-TolC Efflux System |
| title_full | Galactose-Clicked Curcumin-Mediated Reversal of Meropenem Resistance among <i>Klebsiella pneumoniae</i> by Targeting Its Carbapenemases and the AcrAB-TolC Efflux System |
| title_fullStr | Galactose-Clicked Curcumin-Mediated Reversal of Meropenem Resistance among <i>Klebsiella pneumoniae</i> by Targeting Its Carbapenemases and the AcrAB-TolC Efflux System |
| title_full_unstemmed | Galactose-Clicked Curcumin-Mediated Reversal of Meropenem Resistance among <i>Klebsiella pneumoniae</i> by Targeting Its Carbapenemases and the AcrAB-TolC Efflux System |
| title_short | Galactose-Clicked Curcumin-Mediated Reversal of Meropenem Resistance among <i>Klebsiella pneumoniae</i> by Targeting Its Carbapenemases and the AcrAB-TolC Efflux System |
| title_sort | galactose clicked curcumin mediated reversal of meropenem resistance among i klebsiella pneumoniae i by targeting its carbapenemases and the acrab tolc efflux system |
| topic | bliss modelling synergism AcrAB-TolC bla_KPC mCIM eCIM |
| url | https://www.mdpi.com/2079-6382/10/4/388 |
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