GENETIC BASIS OF METABOLITE PRODUCTION AGAINST CLINICALLY-DERIVED PATHOGENS

The World Health Organization declared that new antibiotics are urgently needed to treat carbapenem resistantpathogens. Moreover, mortality from multi-drug resistant (MDR) bacterial infections is projected to cause 10million deaths per year worldwide by 2050, making antibiotic resistance a serious threat. Despite the need fornovel drugs, pharmaceutical companies have dropped research and development interests, primarily due to lowprofitability; thus, antibiotic discovery is of utmost importance. Pseudomonas aeruginosa is a versatileopportunistic pathogen notorious for its role in cystic fibrosis (CF) patients in which a chronic lung infection leadsto a life threating disease, and future effective treatment of MDR P. aeruginosa infections will require novel, yetundiscovered, antibiotics. While much research has been devoted to the pathogenicity of P. aeruginosa,understanding its natural lifecycle should provide insights into important aspects contributing to its susceptibility,as many CF-derived P. aeruginosa originate from ecological isolates. P. aeruginosa strains are repeatedlyobserved to represent an extreme minority of environmentally-derived Pseudomonas populations (i.e., closelyrelated isolates that cluster as distinct phylogenetic groups), suggesting a decreased fitness of P. aeruginosa inhabitats that are distinct from a CF lung. Instead, environments are dominated by other pseudomonads, whoseglobal abundance and omnipresence suggest the expression of certain traits that are advantageous to ecologicalsurvival. A trait that is likely to contribute to such fitness effects is the ability to antagonize nearby competitorsthrough production of antimicrobial factors. Here, the research team proposes that in environments wheremultiple groups of closely related pseudomonads are in sustained competition, such antagonistic interactionslead to decreased fitness of other isolates, such as P. aeruginosa, that are better adapted to and more fit in ahuman host. Thus, investigating direct interactions between environmental bacteria and MDR pathogens shouldprovide the means to identify effective, and novel, antimicrobial factors. Indeed, recent data from the PI showsthat pseudomonads inhibit MDR P. aeruginosa including isolates with carbapenem resistant. Using an innovativeand rigorous culture- based methodology, the hypothesis will be tested by (i) identifying pseudomonads thatinhibit CF-derived MDR pathogens, (ii) characterizing the biosynthetic gene clusters involved in antimicrobialactivity, and (iii) genome analysis of antagonistic strains and biochemical characterization of novel compounds.Results will contribute to detailed characterization of natural antibiotics produced by environmental bacteria thatare effective against MDR pathogens.