Galactose-Clicked Curcumin-Mediated Reversal of Meropenem Resistance among Klebsiella pneumoniae by Targeting Its Carbapenemases and the AcrAB-TolC Efflux System

Antibiotics

MuneshKumar Gupta¹  AshishKumar Singh¹  Pradyot Prakash¹  Shivangi Yadav¹  AkhileshKumar Pandey²  AnandK Agrahari³  Dipshikha Chakravortty⁴  VinodKumar Tiwari⁴ 

[1] Bacterial Biofilm and Drug Resistance Research Laboratory, Department of Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India;Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India;Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India;Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560012, India;

关键词: bliss modelling;    synergism;    AcrAB-TolC;    bla_KPC;    mCIM;    eCIM;   

DOI  :  10.3390/antibiotics10040388

来源: DOAJ

【 摘 要 】

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_aq) 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 Klebsiella pneumoniae 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_aq 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%) Klebsiella isolates were sensitive to meropenem; however, after synergising with Cur_aq (8 µg/mL), 85 (88.54%) hvKP isolates became sensitive to the drug. The Cur_aq also inhibited the AcrAB-TolC efflux system at 1µg/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_aq can be an excellent drug candidate as a broad-spectrum antibacterial and anti-efflux agent.

【 授权许可】

Unknown