Project description:Persisters are rare phenotypic variants that can survive bactericidal doses of antibiotics and resume growth after the conclusion of treatment. They are suspected to be culprits of recurrent infections, and are distinct from resistant mutants because they are genetically identical to bacteria that die from treatment. Persisters to fluoroquinolones (FQs) experience DNA damage from treatment in stationary-phase culture, which suggests that FQs can corrupt their primary target, DNA gyrase, even in these super-tolerant cells. Since DNA damage from FQs originates from its stabilization of DNA gyrase in complexes with cleaved DNA, we hypothesized that the characteristics of FQ-stabilized DNA gyrase cleavage sites (GCS), such as the abundance, and/or location, might be influential to persistence. To test this hypothesis, we measured genome-wide distributions of GCS after treatment with a panel of FQs.We found drug-specific effects on the location and abundances of GCSs and discovered a negative correlation between the number of GCSs and FQ persister levels. Further, additional experiments and analyses suggested that persister levels are not governed by cleavage to a single specific site, but rather survival is a more complex function with respect to GCSs. Together, these findings demonstrate that there are drug specific differences in GCSs that correlate with persister levels, and suggest that the ability of an FQ to stabilize DNA-gyrase complexes at more sites will improve its bactericidal ability.
