Dr. Lewis' team works on the related problems of dormant persister cells and uncultured microorganisms. His drug discovery program derives from these basic studies. Persisters are dormant variants of regular cells that are largely responsible for recalcitrance of chronic infections to antibiotics. He finds that dormancy mechanisms are highly redundant, and in E. coli at least three toxin-antitoxin modules shut down important functions by independent mechanisms. The HipA toxin is a kinase of Ef-Tu, the RelE toxin is an mRNA endonuclease, and TisB forms an ion channel, leading to energy depletion. He and his lab are currently investigating the mechanisms of persister resuscitation in E. coli, and persister formation in other important pathogens – P. aeruginosa, M. tuberculosis, and S. aureus.
Uncultured bacteria are dormant in vitro, and require growth factors produced by their neighbors. We found that in the marine sediment, siderophores act as a common type of growth factors for uncultured species. We recently discovered a second class of growth factors that are required for growth of both environmental organisms and uncultured species of the human microbiome. Uncultured bacteria are an untapped source of secondary metabolites, and we screen them for antibiotic production. Other drug discovery projects are aimed at effective sterilization of microbial cultures to eradicate both growing cells and dormant persisters.