(176ai) Targeting DNA Repair Mechanisms in Bacterial Persisters

Bacterial persisters are phenotypic variants in isogenic bacterial populations that are highly tolerant to antibiotics. Their survival has been attributed to transient growth inhibition during antibiotic treatments, followed by reversal of the process (reawakening or resuscitation) upon removal of the antibiotics. Persisters are thought to underlie the propensity of recurrent infections to relapse and serve as a reservoir from which drug-resistant mutants can emerge (1). Traditional approaches are not sufficient to combat these relapsing infections and it is necessary to develop novel strategies to eliminate these detrimental variants. Previously, it was discovered that persister cells experience antibiotic-induced damage indistinguishable from that seen in antibiotic-sensitive subpopulations, with SOS response and DNA repair mechanisms essential for persister resuscitation (2). To test whether the inhibition of DNA repair mechanisms is detrimental to persister cells during their reawakening process, we screened a small chemical library (mainly composed of FDA approved drugs) using a promoter reporter system that monitors the expression of recA, an essential gene in DNA recombination/repair mechanisms. We identified that a number of drugs including amitriptyline, trifluoperazine, thioridazine, chlorpromazine, hexachlorophene, potassium tellurite and pentachlorophenol are capable of inhibiting the recA expression. We further verified that the identified inhibitors can reduce the expression of other SOS related genes, and eliminate persisters and “viable and non-culturable cells”, another subpopulation of phenotypic variants that are in a non-replicating state and cannot be easily cultured in vitro. Overall, this study shows that targeting persister resuscitation mechanisms holds great potential for eradicating antibiotic tolerant phenotypes.

References

[1] Van den Bergh, Bram, Maarten Fauvart, and Jan Michiels. “Formation, physiology, ecology, evolution and clinical importance of bacterial persisters.” FEMS Microbiology Reviews 41, no. 3 (2017): 219-251.

[2] Völzing KG, Brynildsen MP. 2015. Stationary-phase persisters to ofloxacin sustain DNA damage and require repair systems only during recovery. mBio 6(5):e00731-15. doi:10.1128/mBio.00731-15.