The Repurposing of Pharmaceutical Agents to Improve Treatment Outcomes in Antibiotic-Resistant Bacterial Infections

Bacterial infections continue to exert a tremendous burden on the public health throughout the developing and developed world, in communities and hospitals, and in vulnerable populations such as children, the elderly, surgical patients, the immunocompromised, and those with cancer and other chronic diseases. Over-prescription of antibiotics, extensive antibiotic use in agricultural settings, increasingly complex hospitalized patient populations undergoing treatment have fueled the rise of several highly antibiotic-resistant “superbugs”, exemplified by methicillin-resistant Staphylococcus aureus (MRSA) and multi-drug resistant Pseudomonas aeruginosa, that vex physicians and drive worse patient outcomes. The dependency on the historic success of classical antibiotic therapy, and the lack of financial and market interests towards novel drug development, has contributed to the current fear of a “post-antibiotic era”.As a novel approach to combat invasive and often antibiotic-resistance pathogens such as MRSA and P. aeruginosa, the goal of my thesis research as a dual degree PharmD-PhD student in the Nizet Lab is to identify and develop adjunctive pharmaceutical strategies that improve patient outcomes. Our research group has concluded that the current definition of antibiotic, which only examines direct bactericidal or inhibitory activities on the pathogen, is too narrow and fails to address the fundamental nature of serious human bacterial infections, which are in fact diseases of the host-pathogen interaction. Deficiencies or inflammatory consequences of the immune response and immune cell function drive pathology and severe clinical manifestations, and leading pathogens express multiple virulence determinants (toxins, immune evasion factors) which manipulate the host response to establish disease.By considering the way pharmaceutical agents, antibiotics and non-antibiotics alike, work in the full context of the host-pathogen interaction and innate immune response, we might identify additional opportunities to modify the underlying process to favor bacterial clearance or reduced host tissue injury. These include blocking bacterial virulence factor expression, boosting host innate immune cell bactericidal activities, reducing pathological inflammation, or increasing host cell resiliency. My studies have uncovered two such opportunities in which the unexpected “repurposing” of current FDA-approved drugs demonstrate therapeutic benefit in infections caused by antibiotic-resistant pathogens, uncovering fundamental new biological principles of the host-pathogen interaction in the process