Eradication of Dormant Pathogens
Kim Lewis, Brian Conlon and Michael LaFleur
from: Antibiotics: Current Innovations and Future Trends (Edited by: Sergio Sánchez and Arnold L. Demain). Caister Academic Press, U.K. (2015) Pages: 95-108.
Persisters are specialized survivor cells that protect bacterial and fungal populations from killing by antibiotics. Persisters are dormant phenotypic variants of regular cells rather than mutants. Most microbicidal antibiotics kill by corrupting their targets into producing toxic products; tolerance to antibiotics follows when targets are inactive. Mechanisms of persister formation are redundant, making it difficult to eradicate these cells. In Escherichia coli, toxins RelE and MazF cause dormancy by degrading mRNA; HipA inhibits translation by phosphorylating glutamyl tRNA synthase; and TisB forms an anion channel in the membrane, leading to a decrease in proton motive force (pmf) and ATP levels. Prolonged treatment of chronic infections with antibiotics selects for hip mutants that produce more persister cells. Eradication of tolerant persisters is a serious challenge. Existing antibiotics were developed to kill rapidly growing cells and have limited activity against dormant persisters. A number of compounds were recently described that have a capability of killing persisters. A potentiator of azoles, AC17, sterilizes a biofilm of Candida albicans. Prodrugs are converted into generally reactive compounds with bacteria-specific enzymes and kill growing and dormant cells. Lassomycin activates the ATPase of the ClpP1P2C1 protease of Mycobacterium tuberculosis, and kills persisters. Acyldepsipeptide (ADEP4) activates the ClpP protease, forcing the cell to self-digest, and kills both growing cells and persisters. These findings suggest a path towards developing sterilizing antibiotics read more ...