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.