Elimination of the antimicrobial action of the organoarsenical cancer therapeutic, 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid, before finished product sterility testing

Abstract

Arsenical compounds have been used therapeutically for over 2000 years finding particular relevance as antimicrobials. After being replaced by more selective and consequently less toxic antibiotics in the last century, arsenicals have recently made a resurgence as anticancer drugs (specifically arsenic trioxide and its derivatives). Arsenical parenteral formulations require post-manufacture sterility testing; however, their intrinsic antimicrobial activity must be neutralised before testing to eliminate the possibility of false (no-growth) test results. A range of thiol-containing compounds was screened to establish a suitable deactivation agent for the novel organoarsenical compound, 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO). Dimercatopropanol (DMP) was found to successful deactivate GSAO and was validated according to pharmacopoeial sterility test guidelines (specifically the method suitability test/sterility validation test). DMP is an effective way of deactivating GSAO before sterility testing and can be used for pharmacopoeial sterility tests. Our results affirm previous research highlighting the sensitivity of Staphylococcus aureus to arsenical compounds A method of deactivating the arsenical drug GSAO before the post-manufacture sterility test was established and validated. DMP is a commonly used chelator/deactivation agent so this work may have implications for other inorganic therapeutic agents.