A major focus of my research is on antimicrobial tolerance, which limits the ability of antibiotics to eradicate an infection, and on antimicrobial drug discovery. We discovered that biofilm recalcitrance to treatment is due to the presence of dormant persister cells tolerant to killing by antibiotics. Our research shows that persisters are cells with low levels of ATP, which drops as a result of stochastic variation in expression of energy producing components.
My group has been involved in antimicrobial drug discovery for over a decade. We developed methods to grow uncultured bacteria and to mine them for novel compounds. Of especial interest is teixobactin, a novel cell wall acting antibiotic that binds to different precursors of cell wall polymers and acts without the development of detectable resistance. In addition, lassomycin kills persister cells of M. tuberculosis by forcing the ClpC1 chaperone to deplete ATP. We also discovered that a known antimicrobial compound, ADEP, kills persisters by activating the proteolysis by the Clp protease in S. aureus.
More recently, we refocused our program on the identification of natural compounds acting against Gram negative pathogens, and discovered a new class of antibiotics, darobactins, inhibitors of BamA, an essential protein of the outer membrane, by using differential screening – testing a producer against two different bacterial species (in this case, E. colivs. S. aureus). We also developed an ultra-high-throughput differential screening based on incapsulating a single producer cell in a microdroplet containing two differently fluorescing reporter species. Further development and exploitation of this platform is the subject of the current proposal. Discovery of compounds acting against G- bacteria, and preliminary data on the discovery platform, were developed in the course of work on a recently completed PO1 grant AI118687 (PI/PD, K. Lewis; co-PIs, Karen Nelson, JCVI; Amy Spoering, NovoBiotic); 07/01/16-06/30/21, Resolving the bottleneck in antibiotic discovery.
- Dr. Lewis's personal statement