Biotic activity of Ca2+-modulating non-traditional antimicrobial and -viral agents

INTRODUCTION Combined serendipitous and rational drug-design and -retasking approaches continue to identify many natural and synthetic substances with multipurpose therapeutic properties (Clark, 2013a). Among these substances are Ca2+ modulators capable of attenuating the transmission and severity of viral, bacterial, fungal, and protozoal infections (Clark and Eisenstein, 2013; Clark et al., 2013). The majority of purported Ca2+-modulating antiinfective compounds belong to the functional drug class termed Ca2+channel blockers, including traditional synthetic 1,4-dihydropyridines, phenylalkylamines, and benzodiazepines long approved and marketed for various human and animal cardiovascular and neurological indications (Clark and Eisenstein, 2013; Clark et al., 2013). Additional Ca2+-modulating (putative) antiinfective substances, such as artemisinin, caloxin, dantrolene, cyclosporin A, and FK506, can be further categorized within a broader set of natural and synthetic compounds that affect operation of Ca2+ channels, transporters, exchangers, and/or protein sensors of both hosts and infectious agents (Clark and Eisenstein, 2013; Clark et al., 2013). Notably, depending on chemical structure, site, and mechanism of chemical action, and delivered chemical concentrations, these and other non-traditional antimicrobial and -viral compounds, many of which are expressed by pathogens themselves, may instead exert helpful trophic effects on hosts, their symbiotic microbiota, and harbored mutualistic copathogens. The reasons for such biphasic drug-response profiles partly derive from how pathogens evolved to parasitize host Ca2+-dependent functions and resources, yielding insights into devising better antiinfective treatment regimens and new valued probiotic medicines.