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Development of MRS-2541, a methionyl-tRNA synthetase inhibitor, for Gram positive bacterial infections.

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R44AI134190-04A1
Agency Tracking Number: R44AI134190
Amount: $998,521.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: NIAID
Solicitation Number: PA22-176
Timeline
Solicitation Year: 2022
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-04-25
Award End Date (Contract End Date): 2026-03-31
Small Business Information
540 AVIS DR, STE A
Ann Arbor, MI 48108-7906
United States
DUNS: 156551699
HUBZone Owned: No
Woman Owned: Yes
Socially and Economically Disadvantaged: No
Principal Investigator
 ELKE LIPKA
 (734) 223-6862
 elipka@tsrlinc.com
Business Contact
 ELKE LIPKA
Phone: (734) 223-6862
Email: elipka@tsrlinc.com
Research Institution
N/A
Abstract

The objective of this grant is the preclinical development of MRS-2541, a novel antibiotic structure
targeting Gram+ bacteria by a new mechanism of action. MRS-2541 inhibits bacterial methionyl-
tRNA synthetase required for bacterial protein synthesis, which is very different from its
mammalian counterpart. MRS-2541 is the result of an arduous testing cascade of over 500
compounds requiring broad-spectrum in vitro and in vivo Gram+ activity, a low resistance
frequency and minimal hERG and mitochondrial toxicity.
The initial clinical indication will be acute bacterial skin and skin structure infections (ABSSSI) with
clear endpoints and relatively easy enrollments. MRS-2541 is highly potent against serious
pathogens such as methicillin resistant Staphylococcus aureus (MRSA), vancomycin resistant
Enterococcus faecium (VRE), and Streptococcus species, with minimum inhibitory concentrations
(MICs) ≤ 0.5 µg/mL, which are below those of widely used drugs such as vancomycin and
linezolid. MRS-2541 has minimal cytotoxicity on mammalian cells, is well tolerated in mice at 150
mg/Kg/day, has excellent oral bioavailability, and is as efficacious as linezolid in the S. aureus
and S. pyogenes thigh murine models of infection by both the oral and subcutaneous route.
Specific Aim 1 will be to optimize the new 5-step synthesis from a commercially available
fluorinated precursor and prepare 150 g for Aims 2-4. Aim 2 will characterize the PK/ADME profile
of MRS-2541, including metabolic profiling, cytochrome inhibition, and PK in a non-rodent
species. Aim 3 will more fully characterize the antibacterial profile with MIC90s vs target and some
off-target organisms, as well as the determination of the driver for in vivo efficacy, which is critical
for human dose projections. Finally, Aim 4 will support a GLP 28-day toxicology study in rodents
along with several safety pharmacology studies.
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 MRS-2541 as a clinical lead
candidate, representing a novel antibiotic class to address the critical public health issue of
bacterial drug-resistance not only for ABSSSIs, but for a variety of serious Gram+ infections.

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

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