Induction of antibiotic tolerance in bacteria by self-produced and inter-species signaling
Vega, Nicole M.
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Though most bacteria within a population are killed by high concentrations of antibiotics, tolerant bacteria survive and can re-grow once antibiotics are removed. Bacterial persisters are dormant cells within an isogenic bacterial population that are tolerant to antibiotic treatment and have been implicated in chronic and recurrent infections. Tolerant and persistent bacteria are generated heterogeneously within populations, and a complete understanding of the processes by which these cells are formed remains elusive. However, there is increasing evidence that bacterial communication by chemical signaling plays a role in establishing population heterogeneity. Here I show that bacterial communication induces persistence in Escherichia coli using the self-produced signaling molecule indole. Indole-induced persister formation was monitored using microfluidics, and oxidative stress and phage-shock pathways were determined to play a role in this phenomenon. I propose a model in which indole signaling "inoculates" a bacterial sub-population against antibiotics by activating stress responses, leading to persister formation. Having demonstrated that communication using the signaling molecule indole controls persistence in the intestinal bacterium E. coli, I sought to determine whether indole could be used as an interspecies signal to control antibiotic tolerance in mixed microbial communities. The common bacterial pathogen Salmonella typhimurium was chosen for these experiments because this species, though closely related to E. coli, does not produce indole. The results demonstrated that indole signaling by E. coli induces tolerance to antibiotics in S. typhimurium. Further, the data suggest that indole-induced tolerance in S. typhimurium is mediated at least in part by the phage shock and oxidative stress response pathways, which were previously implicated in control of indole-induced persistence in E. coli. I used C. elegans as a simple in vivo model for gastrointestinal infection with S. typhimurium, demonstrating that indole signaling increased Salmonella tolerance and altered heterogeneity of infection in this system. These results suggest that antibiotic tolerance in pathogens may be induced by interception of bacterial signals in the host environment.
Thesis (Ph.D.)--Boston University