In vitro activity of MRS-2541, a novel MetRS inhibitor, against a selection of resistant gram-positive organisms associated with serious hospital infections.

UNLABELLED: New antibacterials are still needed to treat serious gram-positive hospital infections, including acute bacterial skin and skin structure infections and bloodstream infections. MRS-2541 is a novel type 1 methionyl-tRNA synthetase inhibitor highly selective for gram-positive bacteria. MRS-2541 was evaluated with multiple comparator antibiotics against a large panel of gram-positive organisms enriched with antibacterial-resistant phenotypes. MRS-2541 was the most potent agent against 45 Staphylococcus aureus (SA) (6 SAs, 27 methicillin-resistant Staphylococcus aureus, and 12 vancomycin-intermediate S. aureus) and 35 coagulase-negative staphylococci with MIC90 values of 0.06 and 0.12 µg/mL, respectively, which was superior to all comparators, including vancomycin, linezolid, and daptomycin. MRS-2541 was very potent against 15 Enterococcus faecalis (4-VRE) and 13/15 Enterococcus faecium at ≤0.016 µg/mL, with two insensitive faecium strains (>16 µg/mL). MRS-2541 was less potent against Streptococcus spp., with MIC90 values vs S. pyogenes, S. pneumoniae, and S. sanguinis of 0.5 μg/mL. S. agalactiae and the viridans group streptococci were much less sensitive, with MIC90 values of 8 to >16 µg/mL. These data support MRS-2541 as a new potential option for serious gram-positive hospital infections.

IMPORTANCE: Infections caused by antibiotic-resistant bacteria are inherently challenging to treat. Poor outcomes, including higher death rates, are associated with infections caused by antibiotic-resistant organisms. As a result, there is an urgent need for new antibiotics, particularly ones that act via novel mechanisms that evade established resistance mechanisms. In this paper, we provide new data about MRS-2541, a preclinical antibiotic that acts by inhibiting the bacterial methionyl-tRNA synthetase. We show that MRS-2541 has potent in vitro activity against diverse strains of Staphylococcus, Streptococcus, and Enterococcus. For example, all 115 strains of Staphylococcus spp. (including 27 methicillin-resistant Staphylococcus aureus strains and 12 vancomycin-intermediate S. aureus strains) were fully susceptible to MRS-2541 with MICs of <0.25 μg/mL. The specific activity against gram-positive bacteria and sparing of gram-negative flora indicates that MRS-2541 may be less disruptive of intestinal microbiota than broad-spectrum antibiotics. MRS-2541 is a promising preclinical candidate for infections due to resistant gram-positive organisms.