Antibiotic Resistance

Host-targeted Therapeutics

Host-targeted Therapeutics

Antibiotic resistance is becoming the center of a global healthcare crisis. It is estimated that by 2050, antibiotic resistance will claim ten million lives annually and exert a projected economic burden of $100 trillion. Antibiotics target bacteria, which under high selective pressure, rapidly develop resistance. The overuse of antibiotics in the healthcare and agricultural industries has generated irreversible resistance to drugs that were once effective in treating common bacterial infections. In addition, the development of novel antibiotics has almost completely ceased. With increasing antibiotic resistance and limited treatment options, bacterial infections are once again becoming intractable, leaving a disastrous socio-economic footprint on humans. While much emphasis has been placed on combating bacteria directly, we have taken a different approach; namely, by targeting the host, rather than the pathogen. Unlike conventional pathogen-targeting antibiotics, this host-targeting strategy can prevent and/or treat infections by:

(i) modulating uptake of bacteria by phagocytic host cells

(ii) intercepting host pathways or nutrients utilized by the pathogen during infection

(iii) enhancing the ability of host cells to kill bacteria

Augmenting the ability of host cells to clear invading bacteria provides a promising strategy: our preliminary experiments demonstrate its efficacy in the treatment of infections caused by intracellular bacteria as well as antibiotic-resistant nosocomial infections caused by the so-called “Superbugs”, including Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. As such, we hypothesize that the host-targeting approach can circumvent antibiotic resistance and provide a powerful alternative to antibiotics. We are using chemical and genetic means to enhance the ability of phagocytic immune cells to scavenge, uptake, and kill bacteria, then introduce them into the host either as a prophylactic or therapeutic intervention. Similar cell-based immunotherapy has been successfully applied in cancer treatment, but such a concept has never been explored in the area of infectious diseases. The results of our work are expected to have a positive impact on human health because they will spur the development of new treatments for patients who are predisposed to bacterial infections. Moreover, our results will broaden the current understanding of host-pathogen interaction, which can potentially help in the development of additional therapeutics.