A novel methionyl-tRNA synthetase inhibitor targeting gram-positive bacterial pathogens

Abstract

New antibiotics are needed to treat gram-positive bacterial pathogens. MRS-2541 is a novel inhibitor of methionyl-tRNA synthetase with selective activity against gram-positive bacteria. The minimum inhibitory concentrations (MICs) against Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus species range from 0.063 to 0.5 µg/mL. Given orally to mice at 50 mg/kg every 8 hours, MRS-2541 shows sustained plasma levels well above these MICs. In the mouse thigh infection model, MRS-2541 decreased methicillin-resistant Staphylococcus aureus and Streptococcus pyogenes bacterial loads to the same degree as linezolid. MRS-2541 is a promising new antibiotic for development against skin and soft tissue infections.

Keywords: Staphylococcus; antibiotics; drug discovery; tRNA synthesis.

Fig 1

Chemical structures of MRS-1717, MRS-2144, and MRS-2541. Aqueous solubility measured at pH 7.4.

Fig 2

Pharmacokinetic profile of MRS-2541 in mice given in a single PO dose at 50 mg/kg (mean plasma levels ± SEs, n = 3 mice). MICs (in red) to MRS-2541 for methicillin-susceptible Staphylococccus aureus were tested in broth culture with or without added bovine serum (50%).

Fig 3

Activity of MRS-2541 or linezolid in the neutropenic mouse thigh infection model of MRSA (panels A–C) or S. pyogenes (panel D). Mice received three doses of MRS-2541, linezolid, or vehicle before sacrifice at 24 hours. Compounds administered PO except as shown in panel B. The group labeled “stasis” was sacrificed 2 hours post-infection in untreated mice. Statistics are discussed in the text. mpk, milligrams per kilogram; PO, per os; SC, subcutaneous.

Fig 4

Synthetic scheme for MRS-2541.