1. J Antimicrob Chemother. 2010 Aug;65(8):1720-4. Epub 2010 Jun 9.

Intracellular activity of the peptide antibiotic NZ2114: studies with
Staphylococcus aureus and human THP-1 monocytes, and comparison with daptomycin
and vancomycin.

Brinch KS, Tulkens PM, Van Bambeke F, Frimodt-Møller N, Høiby N, Kristensen HH.

Novozymes A/S, Pharma Discovery, Krogshøjvej 36, DK-2880 Bagsvaerd, Denmark.
kbri@novozymes.com

OBJECTIVES: 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.


PMID: 20534628 [PubMed - in process]