Christina Stallings, PhD
Dissecting Mycobacterial Persistence with Chemical Scalpels
Washington University School of Medicine, St. Louis
The ability of Mycobacterium tuberculosis (Mtb) to withstand antibiotic treatment and host immune pressure has led to a worldwide epidemic of persistent Mtb infection. In order to define ways to target persistent Mtb, in vitro models of mycobacterial persistence must be developed. Toward this end, we have implemented mycobacterial biofilm formation as an in vitro model of persistence. Although there is only limited information supporting a role for Mtb biofilms during pathogenesis, the characteristics of Mtb within a biofilm recapitulate many of the features of bacteria during a persistent infection including stress resistance and tolerance of antibiotic treatment. Using this model, we have identified a family of structurally related small molecules with potent anti-biofilm activities in Mtb and have named these compounds MBIs for Mycobacterial Biofilm Inhibitors. MBIs do not kill or prevent replication of Mtb, indicating that MBIs specifically interfere with a physiological process that is required for the formation of a biofilm. Investigations into the effects of MBIs on Mtb physiology revealed a newly described lipid maturation profile associated with biofilm formation that also occurs during infection and is inhibited by MBI treatment. Inhibition of this developmental change in lipid composition by treatment with MBIs results in changes in proinflammatory cytokine signaling while also sensitizing Mtb to oxidative stress and isoniazid treatment. By using MBIs as chemical scalpels to dissect biofilms, we have revealed new aspects of Mtb physiology and identified potential ways to target protective processes employed by persistent Mtb.