Improving therapy of severe infections through drug repurposing of synergistic combinations

Abstract

Infections from multidrug resistant (MDR) pathogens and emerging viruses present challenges for effective clinical treatments. Drug repurposing and combination screens may provide therapies at a fraction of the time and cost of traditional methods of drug development. Synergistic combinations of two or three known compounds can increase therapeutic efficacy and reduce concentrations required for individual drugs, in turn, reducing the risk of drug toxicity. Using libraries of approved drugs, traditionally non-antibiotic compounds identified in repurposing screens can quickly move into clinical trials, since safety profiles have been previously established. Herein we summarize recent advances in identifying synergistic drug combinations and the use of drug screens for personalized medicine treatments of infections caused by MDR pathogens and emerging viruses.

Figure 1.

Hypothetical workflow for applying repurposing and combinational screens to multi-drug resistant (MDR) gram negative bacteria (GNB) and emerging viruses.

Figure 2.

Schematic representation of multiple mechanism of action (MOA) from the three-drug combination against Ebola Virus (EBV). Posaconazole blocks NAADP-stimulated lysosomal calcium release, the function of NPC protein and ASM activity. Toremifene and mefloquine inhibit NAADP-stimulated lysosomal calcium release and ASM activity. Clarithromycin inhibits NAADP-stimulated lysosomal calcium release.