Identifying Chemical Compounds Targeting Persister Cell's Related Mechanisms in Bacteria

Bacterial persisters are rare, phenotypic variants that are temporarily tolerant to high concentrations of antibiotics. They are generally non-growing cells, and genetically identical to their antibiotic-susceptible kin. These cells are an important health concern because they underlie the proclivity of recurrent infections to relapse, and they serve as a reservoir from which drug resistance mutants can emerge. In fact, recurrent infections account for 65% of hospital-treated infections, and in the US alone it is estimated that they are attributed to half a million deaths, and cost the healthcare system approximately $94 billion per year. Conventional therapies for the recurrent and chronic infections function by targeting the mechanisms that enable the rapid growth of bacterial cell populations. Although this can provide a clinical benefit, this benefit is usually short-lived for these infections and a large body of evidence suggests that persister cells invariably survive this initial selection pressure. Therefore, it is desirable to discover novel compounds that can potentially serve as adjuvants to enhance the persister killing. We approach the problem of persister through inhibiting the SOS response of bacteria under stress. When antibiotics are introduced into the bacterial culture, the cell’s DNA is damaged. Persister cells respond to this DNA damage by inducing the SOS response genes, such as recA, a gene essential for the repair mechanisms of DNA. Inhibition of the SOS response or impairing the DNA repair mechanisms have been found to decrease persister levels. Identifying medicinally relevant chemical compounds that target DNA repair mechanisms so that the cells’ DNA will be permanently damaged can significantly reduce the level of persister cells.