Biology Ph.D. Dissertations

Title

Environmental Pseudomonas are a source of Novel Antibiotics that inhibit Cystic fibrosis derived pathogenic Pseudomonas aeruginosa

Date of Award

2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Biological Sciences

First Advisor

Hans Wildschutte (Advisor)

Second Advisor

Robert McKay (Committee Member)

Third Advisor

Paul Morris (Committee Member)

Fourth Advisor

Scott Rogers (Committee Member)

Fifth Advisor

Kurt Panter (Other)

Abstract

The emergence of antimicrobial resistance bacteria has become a major threat to human society. The rapid spread of resistant pathogens and the associated loss of efficacy of available drugs needs to be met with the development of antibiotics and alternative treatments. Pseudomonas aeruginosa is an opportunistic human pathogen evolving resistance to many currently used antibiotics. Chronic lung infections with the bacterium P. aeruginosa are the leading cause of morbidity and mortality in cystic fibrosis (CF) patients. Escalating this problem is that pharmaceutical companies have dropped drug development due to low profitability, thus making the efforts of drug discovery of prime importance. To address this global health threat research institutes have now stepped forward to aid in discovery of novel compounds. P. aeruginosa dominates the lungs during chronic infections in CF patients, yet it’s abundance in non-human habitats such as water and soil is less compared to other diverse groups of pseudomonads. A trait that could contribute to such decreased abundance is bacterial competition from other Pseudomonas populations that dominate water and soil habitats. We hypothesized that environmental Pseudomonas from diverse soil and water habitats produce secondary metabolites capable of inhibiting the growth of CF derived P. aeruginosa. Here, we sought to determine if clinical isolates of P. aeruginosa are susceptible to competition by environmental pseudomonads which may provide a source of inhibitory factors. We have used a population based study in association with transposon mutagenesis, PCR techniques, whole genome sequencing and bioinformatic analysis to identify environmental Pseudomonas biosynthetic gene clusters (BGCs) and characterize antagonistic compounds that are effective against CF-derived P. aeruginosa. A total of five BGCs have been identified in this study from environmental Pseudomonas strains S4B6, S3F9 (soil-derived) and LE6C6 (water-derived) encoding diverse compounds such as bacteriocins, NRPSs, phenazines, and siderophores involved in antagonistic activity. Extending this analysis, we have also identified environmental Pseudomonas that inhibit not only CF-derived P. aeruginosa but are effective against other pathogens including ESKAPE pathogens and carbapenem resistant P. aeruginosa. Overall, this research serves as a platform for the identification of novel antibiotics from these environmental isolates.

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