Development of methionyl tRNA synthetase inhibitors for Gram positive bacterial infections

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R44AI134190-01
Agency Tracking Number: R44AI134190
Amount: $1,000,000.00
Phase: Phase II
Program: SBIR
Awards Year: 2017
Solicitation Year: 2014
Solicitation Topic Code: NIAID
Solicitation Number: PAR14-088
Small Business Information
540 AVIS DR STE A, Ann Arbor, MI, 48108-7906
DUNS: 156551699
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 ELKE LIPKA
 (734) 223-6862
 elipka@tsrlinc.com
Business Contact
 ELKE LIPKA
Phone: (734) 663-4233
Email: elipka@tsrlinc.com
Research Institution
N/A
Abstract
The objective of this research is to develop a novel antibiotic targeting Gram positive bacteria with an initial clinical indication of acute bacterial skin and skin structure infections ABSSSI The research will address the urgent problem of antibiotic resistant bacteria that are spreading around the world The new antibiotic is being designed to inhibit a novel target the bacterial methionyl tRNA synthetase enzyme that is required for protein synthesis The type of enzyme found in Gram positive bacteria is different from the comparable enzyme in the human cytoplasm thus making it possible to design selective and safe inhibitors In preliminary studies we have identified highly potent compounds against serious pathogens such as methicillin resistant Staphylococcus aureus MRSA vancomycin resistant Enterococcus faecium VRE Streptococcus species and others The minimum inhibitory concentrations MICs are below those of widely used drugs such as vancomycin and linezolid The compounds have minimal toxicity on mammalian cells are well tolerated in mice are orally available and show efficacy in two mouse model of Staphylococcus infection comparable to linezolid Specific Aim will be to optimize the antibacterial pharmacological and safety properties of the compound in order to select a preclinical candidate Approximately new compounds will be synthesized and tested according to a screening cascade The selected compound will pass safety tests such as Ames and hERG inhibition and will demonstrate potent activity in the murine model of Staphylococcus infection Specific Aim will involve PK ADME in vivo efficacy testing in mice and in vitro toxicology studies to allow for identification of a lead candidate This will be followed by definitive PK and exploratory toxicology studies in rats and evaluation of the lead candidate in additional efficacy studies Aim The scientific teams at University of Washington and TSRL have the combined expertise in chemistry microbiology pharmacology and preclinical drug development to execute the proposed research plan A successful project will bring forward a candidate drug in a novel antibiotic class to address the critical public health issue of bacterial drug resistance Infections due to antibiotic resistant bacteria are spreading throughout the world and represent a major threat to public health The goal of this project is to develop a new antibiotic acting by a novel mechanism that will provide a new option for treating drug resistant bacterial infections

* Information listed above is at the time of submission. *

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