Formulation of host-targeted therapeutics against bacterial infections

The global burden of bacterial infections is rising due to increasing resistance to the majority of first-line antibiotics, rendering these drugs ineffective against several clinically important pathogens. Limited transport of antibiotics into cells compounds this problem for gram-negative bacteria that exhibit prominent intracellular lifecycles. Furthermore, poor bioavailability of antibiotics in infected tissues necessitates higher doses and longer treatment regimens to treat resistant infections. Although emerging antibiotics can combat these problems, resistance still may develop over time. Expanding knowledge of host-pathogen interactions has inspired research and development of host-directed therapies (HDTs). HDTs target host-cell machinery critical for bacterial pathogenesis to treat bacterial infections alone or as adjunctive treatment with traditional antibiotics. Unlike traditional antibiotics that directly affect bacteria, a majority of HDTs function by boosting the endogenous antimicrobial activity of cells and are consequently less prone to bacterial tolerance induced by selection pressure. Therefore, HDTs can be quite effective against intracellular cytosolic or vacuolar bacteria, which a majority of traditional antibiotics are unable to eradicate. However, in vivo therapeutic efficacy of HDTs is reliant on adequate bioavailability. Particle-based formulations demonstrate the potential to enable targeted drug delivery, enhance cellular uptake, and increase drug concentration in the host cell of HDTs. This review selected HDTs for clinically important pathogens, identifies formulation strategies that can improve their therapeutic efficacy and offers insights toward further development of HDTs for bacterial infections.