Small-molecule inhibitors of bacterial metallo-β-lactamases
The main focus of the thesis is the discovery and development of novel inhibitors of bacterial metallo-β-lactamases (MBLs).
- Hajmohammadebrahimtehrani, K.
- 16 december 2020
- Thesis in Leiden Repository
The main focus of the thesis is the discovery and development of novel inhibitors of bacterial metallo-β-lactamases (MBLs). Chapter 1 provides an overview of FDA-approved β-lactamase inhibitors as well as those currently being evaluated in clinical trials. Chapters 2 and 3 describe our evaluation of small-molecule aminocarboxylic acids either commercially available or prepared via chemoenzymatic approaches for their activity against clinically important MBLs. We found that nitrilotriacetic acid and its phosphonic acid isostere, as well as ethylenediamine-N,N′-disuccinic acid (EDDS), are potent inhibitors of New-Delhi metallo-beta-lactamase (NDM-1). Focusing on another class of MBL inhibitors, chapter 4 describes our study of selected thiol-containing compounds. Among them, thiomandelic acid showed the most potent and broad-spectrum synergistic activity when combined with meropenem against MBL-producing gram-negative bacteria. Stability studies, however, showed that thiomandelic acid is oxidized to its corresponding disulfide with the half-life of ca. 5 h. To address the stability and selectivity issue associated with thiols, in chapter 5 we describe a prodrug approach where we synthesized and evaluated a series of thiol conjugates of cephalosporins. Some of these cephalosporin conjugates exhibit potent inhibition of IMP class of MBLs. Finally, chapter 6 describes our biochemical evaluation of a newly identified class A carbapenemase.