Beta-lactamase mediated bacterial resistance represents one of the most persistent challenges to antibiotic chemotherapy. In anticipation of a clinical threat from metallo- beta-lactamases, there is need for potent inhibitors of the clinically relevant class B1 metallo-beta-lactamases (MBL). Current MBL inhibitors have only been tested and developed for one clinically relevant class B1 MBL, IMP-1, or less clinically relevant MBLs. Most important to our research endeavor is that an array of potent inhibitors has not been developed or described for VIM-2. This class B1 MBL is second only to IMP-1 in its clinical relevance. The preliminary goal of this effort is to establish a novel FRET-based HTS assay to identify inhibitors of VIM-2. Using a traditional HTS research operating plan, we will use a nitrocefin-based assay will be used to identify compounds that may be artifact in the FRET-based assay. To probe whether a compound active in the VIM-2 assay has potential utility as a broad-spectrum MBL inhibitor, an IMP-1 assay will also be developed & implemented. We feel that our HTS-based approach will not only rapidly discover probes, but also help triage those probes before proceeding to antibiotic potentiation assays. Our long term objective is to design MBL class B1 chemical probes. We will begin this endeavor by screening our in-house """"""""click-chemistry"""""""" library, from Professor Barry Sharpless' research laboratory, against VIM-2. The inhibitors found in this assay will have """"""""spring-loaded"""""""" moieties that promote straightforward and rapid SAR studies. Through screening of larger compound libraries, e.g. the MLSCN compound collection, the results of both activities should have an impact on VIM-2 related research by providing publicly available or easily synthesized VIM-2 probes. By modifying the probes to have broad spectrum inhibition, we plan to further advance the clinical relevance of our research. The diversity of infectious bacteria continues to outpace the development of novel drugs to treat them. Often bacteria appear to be resistant to traditional antibiotics. Beta lactamases are bacterial enzymes that are responsible for resistance to many antibiotics. Our goal is to develop several high throughput screening assays suitable for rapid identification of novel drugs that modulate the activity of beta-lactamases. In consort with Prof. Barry Sharpless (TSRI: Dept of Chemistry), we will screen """"""""click-chemistry"""""""" libraries for a synergistic and novel approach to the rapid synthesis and discovery of beta-lactamase inhibitors. ?
| Weide, Timo; Saldanha, S Adrian; Minond, Dmitriy et al. (2010) NH-1,2,3-Triazole-based Inhibitors of the VIM-2 Metallo-?-Lactamase: Synthesis and Structure-Activity Studies. ACS Med Chem Lett 1:150-154 |
| Minond, Dmitriy; Saldanha, S Adrian; Subramaniam, Prem et al. (2009) Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries. Bioorg Med Chem 17:5027-37 |
