P0726 Paper Poster Session IV Drug discovery - Gram-positives AP138, a second-generation plectasin, shows improved and potent in vitro activity against Gram-positive

S. Lociuro1, S. Neve2, P. Nordkild2 1Adenium Biotech, Rancate, Switzerland 2Adenium Biotech, Copenhagen, Denmark

Objective AP114 (formerly known as NZ2114) is a bactericidal 40-amino acid anti-microbial derived from plectasin, a natural isolated from nigrella. Plectasin, discovered by Novozymes in 2004, was shown to exert it mechanism of action by directly binding the bacterial cell-wall precursor Lipid II (Schneider T. et al. Science. 2010; 328:1168-1172) and hence inhibiting cell wall biosynthesis.AP138 is the result of an extensive lead optimisation program based on a set of in silico generated plectasin variants. Here we wish to report the MICs of the plectasin second-generation AP138 against a recent collection of clinical isolates of Staphylococcus aureus, Staphylococcus spp, agalactiae, Streptococcus pyogenes and in comparison with the first-generation AP114, vancomycin, daptomycin and linezolid. Methods:MICs were determined in accordance with Clinical Laboratory Standard Institute (CLSI) guidelines M07-A9 for aerobic (staphylococci and streptococci). Mueller-Hinton broth (MH) was used for culture of staphylococci, and this was supplemented with 5% lysed horse blood (MHB) for the culture of streptococci. Results:Recent clinical isolates of Gram-positive bacteria including multi-resistant clinical isolates of Staphylococcus aureus (N=82), Staphylococcus spp (N=30), Streptococcus agalactiae (N=30), Streptococcus pyogenes (N=30) and Streptococcus pneumoniae (N=30) were investigated. The Table below reports MIC50, MIC90 and MIC range data for AP138 and AP114. The results showed that AP138 exhibited a very potent effect against clinical isolates of Staphylococcus aureus against which was generally more active than first generation AP114.

Conclusion: The clinical candidate AP138 showed very potent activities against a recent collection of Gram-positive pathogens against which showed MIC90s comprised between 0.5 and 8 µg/ml.