Author(s): Shaan Patel*, Pradip Jadav*, Rajesh Bahekar, Kumargurubaran Nagaswamy, Kasinath Viswanathan, Purvi Vyas, Poonam Giri, S. Sachchidanand and Mukul Jain
Page: [3506 - 3514] Pages: 9
* (Excluding Mailing and Handling)
Background: Prevalence of microbial resistance due to Metallo-β-lactamase (MBL) enzyme pose a serious threat to human life. MBLs depend on active site zinc for their hydrolytic activity; hence, the investigation of zinc chelators emerged as an attractive strategy for the development of potent MBL inhibitors.
Methods: To prove that such chelators selectively target MBLs, in the present investigation, novel cephalosporins based MBL inhibitors (Cef-MBLi) were designed as a conjugate of cephalosporins with a potent zinc binder 8-thioquinoline (8-TQ).
Results: Cef-MBLi showed site specific release of conjugate only in the presence of a Veronaintegron encoded metallo-β-lactamase 2 (VIM-2) bacterial enzyme through hydrolytic cleavage mechanism. A total of 6 (4a-e and 6f) New Chemical Entities (NCE’s) were prepared, characterized and subjected for in vitro study.
Conclusion: Among tested NCE’s, 4c showed potent MBL inhibitory activity against the VIM-2 enzyme.
Keywords: Antibiotic (Abs), antibiotic resistance, metallo-β-lactamase (MBL) enzymes, 8-thioquinoline (8-TQ), cephalosporin based MBL inhibitors (Cef-MBLi), conjugates, enzyme inhibition.
Download PDF Flyer