Intracellular activity of the peptide antibiotic NZ2114: studies with Staphylococcus aureus and human THP-1 monocytes, and comparison with daptomycin and vancomycin.
OBJECTIVE
Staphylococcus aureus survives inside eukaryotic cells. Our objective was to assess the activity of NZ2114, a novel peptidic antibiotic, against intracellular S. aureus in comparison with established antistaphylococcal agents acting on the bacterial envelope with a distinct mechanism.


METHODS
The extracellular (broth) and intracellular (THP-1 monocytes) activities of NZ2114 were compared with those of vancomycin and daptomycin against methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA).


RESULTS
All three compounds showed an extracellular bactericidal effect (>3 log(10) kill) against MSSA and MRSA. Daptomycin and NZ2114 also exhibited bactericidal activity against VRSA. The extracellular killing was concentration dependent for all three compounds within the range of drug concentrations tested. The intracellular experiments demonstrated a maximal intracellular effect of NZ2114 after 24 h as a 5 log(10) cfu reduction against MSSA (ATCC 25923), while the activity was a 0.9 log(10) cfu reduction against MRSA and a 0.2 log(10) cfu reduction against VRSA. For comparison, the intracellular activity of daptomycin was a 1.0 log(10) cfu reduction against MSSA, a 0.8 log(10) cfu reduction against MRSA and a 0.3 log(10) cfu reduction against VRSA. Vancomycin showed activity against both MSSA and MRSA (0.6 log(10) cfu reduction), whereas VRSA was resistant to vancomycin.


CONCLUSIONS
NZ2114 displayed similar extracellular and intracellular activities as daptomycin, and was more effective than vancomycin against the intracellular forms of susceptible bacteria. However, the study also showed that the intracellular activities of NZ2114 and daptomycin are weaker than their extracellular activities.
Novozymes A/S, Pharma Discovery, Krogshøjvej 36, DK-2880 Bagsvaerd, Denmark. kbri@novozymes.com
Karoline Sidelmann
KS
Brinch
Paul M
PM
Tulkens
Francoise
F
Van Bambeke
Niels
N
Frimodt-Møller
Niels
N
Høiby
Hans-Henrik
HH
Kristensen
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002460:Cell Line; D015169:Colony Count, Microbial; D017576:Daptomycin / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D009000:Monocytes / Q000382:microbiology*; D010455:Peptides / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects*; D014640:Vancomycin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D010455:Peptides; D014640:Vancomycin; D017576:Daptomycin