title: Antimicrobial properties of MX-2401, an expanded-spectrum lipopeptide active in the presence of lung surfactant.
abstract: MX-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 against Enterococcus spp., including vancomycin-sensitive Enterococcus (VSE), vanA-, vanB-, and vanC-positive vancomycin-resistant Enterococcus (VRE), linezolid- and quinupristin-dalfopristin-resistant isolates (MIC(90) of 4 μg/ml), methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) (MIC(90) of 2 μg/ml), coagulase-negative staphylococci, including methicillin-sensitive Staphylococcus epidermidis (MSSE) and methicillin-resistant S. epidermidis (MRSE) (MIC(90) of 2 μg/ml), and Streptococcus spp. including viridans group streptococci, and penicillin-resistant, penicillin-sensitive, penicillin-intermediate and macrolide-resistant isolates of Streptococcus pneumoniae (MIC(90) of 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 against S. aureus and Enterococcus 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 affected in vitro by the presence of lung surfactant, and MX-2401 was active in vivo in 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 Ca(2+) 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.
authors.affiliation: BioWest Therapeutics Inc., Suite 1320, 885 West Georgia, Vancouver, British Columbia, Canada V6C 2G2.
authors.forename: Dominique
authors.initials: D
authors.lastname: Dugourd
authors.forename: Haiyan
authors.initials: H
authors.lastname: Yang
authors.forename: Melissa
authors.initials: M
authors.lastname: Elliott
authors.forename: Raymond
authors.initials: R
authors.lastname: Siu
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Clement
authors.forename: Suzana K
authors.initials: SK
authors.lastname: Straus
authors.forename: Robert E W
authors.initials: RE
authors.lastname: Hancock
authors.forename: Evelina
authors.initials: E
authors.lastname: Rubinchik
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002118:Calcium / Q000032:analysis; D002942:Circular Dichroism; D017576:Daptomycin / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial; D016983:Enterococcus / Q000187:drug effects*; D005260:Female; D055666:Lipopeptides / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D019906:Nuclear Magnetic Resonance, Biomolecular; D018410:Pneumonia, Bacterial / Q000188:drug therapy; D037661:Pulmonary Surfactant-Associated Proteins / Q000494:pharmacology*; D013210:Staphylococcus / Q000187:drug effects*; D013291:Streptococcus / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D055666:Lipopeptides; C556453:MX-2401; D037661:Pulmonary Surfactant-Associated Proteins; D017576:Daptomycin; D002118:Calcium