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: Dominique Dugourd, Haiyan Yang, Melissa Elliott, Raymond Siu, Jacob J Clement, Suzana K Straus, Robert E W Hancock, Evelina Rubinchik
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 55 Issue 8 Pg. 3720-8 (Aug 2011) ISSN: 1098-6596 [Electronic] United States
• PMID: 21576435 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Lipopeptides
• MX-2401
• Pulmonary Surfactant-Associated Proteins
• Daptomycin
• Calcium

Topics

• Animals
• Anti-Bacterial Agents (pharmacology)
• Calcium (analysis)
• Circular Dichroism
• Daptomycin (pharmacology)
• Drug Resistance, Multiple, Bacterial
• Enterococcus (drug effects)
• Female
• Lipopeptides (chemistry, pharmacology)
• Mice
• Microbial Sensitivity Tests
• Nuclear Magnetic Resonance, Biomolecular
• Pneumonia, Bacterial (drug therapy)
• Pulmonary Surfactant-Associated Proteins (pharmacology)
• Staphylococcus (drug effects)
• Streptococcus (drug effects)