All bacterial populations stochastically produce a small number of dormant persister cells tolerant to antibiotics. Persisters are not mutants but phenotypic variants of the wild type.
We are interested in discovering the mechanism of persister formation. Using cell sorting and transcriptome analysis, we find that chromosomally-encoded “toxin” genes act to shut down cellular functions, creating a dormant state. Examples include HipA, which encodes a protein kinase that phosphorylates elongation factor Ef-Tu, blocking protein synthesis, and TisB, a small peptide that inserts in the membrane, causing a drop in pmf and ATP levels. Interestingly, TisB synthesis is induced by DNA damaging agents, including fluoroquinolone antibiotics. This means that persisters can be formed not only stochastically, but through stress response mechanisms.
We find that in chronic infections such as cystic fibrosis, antibiotic treatment selects for high-persister mutants. Whole genome sequencing indicates the mechanism for increased production of persisters.
Current projects involve the study of the molecular mechanisms of persister formation governed by HipA and TisB in E. coli; the search for persister genes in P. aeruginosa, S. aureus and M. tuberculosis; and characterization of high-persister mutants from clinical isolates of these pathogens. A related project is discovery of compounds capable of eliminating persisters. The work of the persister group is supported by a Transformative Award from the NIH, and with grants from ARO and CF Foundation.