The antimicrobial activity of innate host-directed therapies: A systematic review

Intracellular human pathogens are the deadliest infectious diseases and are difficult to treat effectively due to their protection inside the host cell and the development of antimicrobial resistance (AMR). An emerging approach to combat these intracellular pathogens is host-directed therapies (HDT), which harness the innate immunity of host cells. HDT rely on small molecules to promote host protection mechanisms that ultimately lead to pathogen clearance. These therapies are hypothesized to: (1) possess indirect yet broad, cross-species antimicrobial activity, (2) effectively target drug-resistant pathogens, (3) carry a reduced susceptibility to the development of AMR and (4) have synergistic action with conventional antimicrobials. As the field of HDT expands, this systematic review was conducted to collect a compendium of HDT and their characteristics, such as the host mechanisms affected, the pathogen inhibited, the concentrations investigated and the magnitude of pathogen inhibition. The evidential support for the main four HDT hypotheses was assessed and concluded that HDT demonstrate robust cross-species activity, are active against AMR pathogens, clinical isolates and laboratory-adapted pathogens. However, limited information exists to support the notion that HDT are synergistic with canonical antimicrobials and are less predisposed to AMR development.