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Discovering Linearmycins in Bacterial Competition: Lysis, Autolysis, and Resistance
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Throughout history, especially beginning in the mid-twentieth century, humans have adapted numerous specialized metabolites produced by microbes as therapeutics. Since their inception, antibiotics have been a powerful tool used in science and medicine. We have uncovered a great deal about the cellular functions that antibiotics target, mechanisms of resistance, and their application in treating disease. However, there are still gaps in our understanding of the ecological function and roles of specialized metabolites. Additionally, in recent years we’ve begun to appreciate the importance of microbial communities in diverse environmental settings, including the human microbiome. The structure and maintenance microbial communities resulting from networks of competitive interactions and are driven by many factors including the production and response to antibiotics and other specialized metabolites. Currently, whole microbial communities are not tractable to study. To address fundamental questions relating to the fitness of members in a community I use a model competitive system with two soil bacteria: Bacillus subtilis and Streptomyces sp. Mg1 (S. Mg1). On an agar surface, colonies of B. subtilis lyse and degrade in response to S. Mg1 cultured at a distance. In this dissertation, I determined that B. subtilis lysis is caused by the family of polyketides known as linearmycins. I obtained mutants of B. subtilis that were spontaneously resistant to linearmycins and formed biofilms. Each resistant mutant that I identified had a missense mutation in yfiJK, which encodes a previously uncharacterized two-component signaling system. In response to linearmycin exposure, I found that the YfiJK system activates expression of the yfiLMN operon. This operon encodes an ATP-binding cassette transporter that is both necessary and sufficient for both the linearmycin resistance and biofilm formation phenotypes of the yfiJK mutants. Finally, I determined that linearmycin biosynthesis and expression of the linearmycin (lny) biosynthetic gene cluster are coordinated during S. Mg1 growth. In particular, we observe an increase in both linearmycins and extracellular vesicles during stationary phase, suggesting an autolytic origin for linearmycin-laden extracellular vesicles produced by S. Mg1. Together, my results demonstrate that coordinated regulation of developmental processes including autolysis, biofilm formation, and motility with specialized metabolism and antibiotic resistance promote competitive fitness of bacteria.
Stubbendieck, Reed Michael (2017). Discovering Linearmycins in Bacterial Competition: Lysis, Autolysis, and Resistance. Doctoral dissertation, Texas A & M University. Available electronically from