Identifying Chemical Compounds Targeting Persister 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 are genetically identical to their antibiotic-susceptible kin. These cells are an important health concern because they underlie the proclivity of the relapse of recurrent infections, and they can serve as a reservoir from which drug-resistance mutants can emerge. It is believed that persister cells survive quinolone antibiotic treatment by activating their DNA repair mechanisms, such as recA, which is an essential protein for the repair of the damaged DNA. It has been found that impairment of the DNA repair mechanisms could significantly decrease persistence. Therefore, it is desirable to discover medicinally relevant chemical compounds that target bacterial DNA repair mechanisms to serve as adjuvants to enhance antibiotic effect. In this project, we developed a rapid and efficient method to screen for potential chemical inhibitors. From the Phenotype MicroArrays chemical library from Biolog Inc. (Hayward, CA), we were able to identify a number of FDA-approved chemical compounds that can serve as inhibitors of the bacterial cells' DNA repair mechanisms, thus eliminate persistence without independently eradicating the cell cultures.