Metabolism of small antimicrobial β2,2-amino acid derivatives by murine liver microsomes

We have investigated the in vitro metabolism of three small antimicrobial β2,2-amino acid derivatives (M w < 500) that are highly potent against methicillin resistant Staphylococcus aureus, and are among the first compounds designed from small cationic antimicrobial peptides with potential for oral administration. The β2,2-amino acid derivatives are virtually completely resistant against degradation by proteases, and to further explore their drug potential, we have investigated the hepatic Phase I metabolism of this class of antimicrobial compounds. The β2,2-amino acid derivatives were incubated with murine liver microsomes and the metabolites analyzed semi-quantitatively by HPLC–MS and qualitatively by ultra performance liquid chromatography coupled to a tandem mass spectrometer which enabled identification of the metabolites by careful interpretation of the collision activated dissociation spectra. The study shows that sterically hindered β2,2-amino acid derivatives that otherwise are stable against proteolytic degradation underwent Phase I metabolism and were oxidized to a number of different metabolites depending on the structure of the β2,2-amino acid side-chains.