Antimicrobial Properties of MX-2401, an Expanded-Spectrum Lipopeptide Active in the Presence of Lung Surfactant

Abstract

ABSTRACTMX-2401 is an expanded-spectrum lipopeptide antibiotic selective for Gram-positive bacteria that is a semisynthetic analog of the naturally occurring lipopeptide amphomycin. It was active againstEnterococcusspp., including vancomycin-sensitiveEnterococcus(VSE),vanA-,vanB-, andvanC-positive vancomycin-resistantEnterococcus(VRE), linezolid- and quinupristin-dalfopristin-resistant isolates (MIC90of 4 μg/ml), methicillin-resistantStaphylococcus aureus(MRSA) and methicillin-sensitiveS. aureus(MSSA) (MIC90of 2 μg/ml), coagulase-negative staphylococci, including methicillin-sensitiveStaphylococcus epidermidis(MSSE) and methicillin-resistantS. epidermidis(MRSE) (MIC90of 2 μg/ml), andStreptococcusspp. including viridans group streptococci, and penicillin-resistant, penicillin-sensitive, penicillin-intermediate and macrolide-resistant isolates ofStreptococcus pneumoniae(MIC90of 2 μg/ml). MX-2401 demonstrated a dose-dependent postantibiotic effect varying from 1.5 to 2.4 h. Furthermore, MX-2401 was rapidly bactericidal at 4 times the MIC againstS. aureusandEnterococcus faecalis, with more than 99.9% reduction in viable bacterial attained at 4 and 24 h, respectively. The MICs of MX-2401 against MRSA, MSSA, VSE, and VRE strains serially exposed for 15 passages to sub- to supra-MICs of MX-2401 remained within three dilutions of the original MIC. In contrast to that of the lipopeptide daptomycin, the antibacterial activity of MX-2401 was not affectedin vitroby the presence of lung surfactant, and MX-2401 was activein vivoin the bronchial-alveolar pneumonia mouse model, in which daptomycin failed to show any activity. Moreover, the activity of MX-2401 was not as strongly dependent on the Ca2+concentration as is the activity of daptomycin. In conclusion, MX-2401 is a promising new-generation lipopeptide for the treatment of serious infections with Gram-positive bacteria, including hospital-acquired pneumonia.