Grant: Foundation Grant

Antibiotics are the most successful medical intervention in human history. They are critical for preventing and treating life-threatening infections. A lack of effective antibiotics would lead to difficulties with major surgeries, chemotherapy, transplantations, and early-term births; even minor injuries could become infected and deadly. Thus the relentless and concerning increase in multi-drug resistance to antibiotics in the face of a inadequate pipeline for new antibiotics has caused great concern for public health officials and the general public. Indeed, in Sept 2016, all 193 member countries of the United Nations declared antimicrobial resistance "the biggest threat to modern medicine". Here we will investigate the mechanisms of adaptive, multiple-antibiotic resistance in the important pathogen Pseudomonas aeruginosa, one of the most difficult to treat bacterial "Superbugs" in our society. Adaptive resistance is a feature of specific bacterial "lifestyles" that are triggered during growth in patients; we will investigate the mechanisms of such resistance in the context of growth circumstances that occur during infections. To tackle adaptive and acquired resistance and provide new therapies that address the poor success of modern antibiotic discovery, we will then develop three alternatives to antibiotics: 1) Novel anti-biofilm peptides to treat adaptive multiple-antibiotic resistance due to the growth of bacteria on body surfaces as multicellular colonies termed biofilms (representing two thirds of all hospital infections); 2) Peptides that enhance the anti-infection properties of the immune system; and 3) Compounds that will reverse the inability of the immune system to respond to pathogens in patients with sepsis (causes 8% of all deaths worldwide). A feature of these strategies is that they will assist in making available antibiotics work better. Our research will move our discoveries to clinical testing during the funding period.