Multi-drug resistance in Enterobacteriaceae is regarded as a healthcare crisis. While carbapenems are among the most prescribed antibiotics for infections caused by these organisms, carbapenem resistance conferred by zinc-based metallo-carbapenemases (Amber Class B) is a growing global health concern that threatens to erode the efficacy of these antibiotics both in the hospital and community settings. Members of this family of resistance enzymes such as NDM-1 are found on promiscuous plasmids with other MDR resistance mechanisms, and are rapidly spreading throughout Enterobacteriaceae. The concern now is that, in the absence of clinically available MBL inhibitors (i.e. MBLs are refractory to clinically available legacy inhibitors tazobactam, clavulanic acid and sulbactam), MBLs such as NDM-1 could become the dominant carbapenemases in clinical settings. As there are currently no MBL inhibitors in pharmaceutical development, there is an urgent need to progress compounds into the drug development pipeline to address this growing issue and safeguard carbapenems. In the Phase I work, we identified a pre-development candidate, VNRX-5113, meeting or exceeding established success criteria including potent and selective inhibitory activity against NDM-1 and VIM MBLs, rescue of Meropenem activity in recent and representative NDM/VIM-producing clinical isolates of Enterobacteriaceae, P. aeruginosa and A. baumannii, established in vivo efficacy in a murine septicemia model and preliminary pharmacokinetics compatible with t.i.d. dosing with Meropenem. We also identified 4 potential backup compounds to VNRX-5113 as contingencies. The Phase II application endeavors to drive this """"""""first in class"""""""" MBL inhibitor candidate (VNRX-5113) through IND-enabling studies to an Investigational New Drug filing.

Public Health Relevance

Metallo-?-lactamase enzymes such as NDM-1 and VIM-variants are spreading throughout Enterobacteriaceae and pose a serious threat to ?-lactam efficacy in both the hospital and community settings. The increased use of generic carbapenems will impose further selective pressure for these enzymes. As there are currently no available inhibitors for Metallo ? -lactamases (MBLs), nor any prospects in pharmaceutical development, the future utility of carbapenems is uncertain. To address this medical need, we have selected a pre-development candidate MBL inhibitor (VNRX-5113) with potent inhibitory activity against NDM-1 and VIM-variants, capable of rescuing meropenem activity in NDM/VIM-producing clinical isolates of Enterobacteriaceae and select non- fermenters (Pseudomonas aeruginosa and Acinetobacter baumannii). We believe that VNRX-5113 will fill the gap in ?-lactamase coverage and safeguard the future utility of carbapenems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44AI096613-04
Application #
8686735
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Xu, Zuoyu
Project Start
2011-09-21
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Venatorx Pharmaceuticals, Inc.
Department
Type
DUNS #
City
Malvern
State
PA
Country
United States
Zip Code
19355