Summary
The multidrug-resistant, opportunistic pathogen, Acinetobacter baumannii, has spread swiftly through hospitals worldwide. Previously, we demonstrated that A. baumannii regulates the expression of various genes in response to DNA damage. Some of these regulated genes, especially those encoding the multiple error-prone DNA polymerases, can be implicated in induced mutagenesis, leading to antibiotic resistance. Here, we further explore the DNA damage-inducible system at the single cell level using chromosomal transcriptional reporters for selected DNA damage response genes. We found the genes examined respond in a bimodal fashion to ciprofloxacin treatment, forming two phenotypic subpopulations: induced and uninduced. This bimodal response to ciprofloxacin treatment in A. baumannii is unique and quite different than the Escherichia coli paradigm. The subpopulations are not genetically different, with each subpopulation returning to a starting state and differentiating with repeated treatment. We then identified a palindromic motif upstream of certain DNA damage response genes, and have shown alterations to this sequence to diminish the bimodal induction in response to DNA damaging treatment. Lastly, we are able to show a biological advantage for a bimodal response, finding that one subpopulation survives ciprofloxacin treatment better than the other.
Current knowledge about bacterial DDRs is based off of Escherichia coli, where the global SOS repressor, LexA, controls genes involved in the response to DNA damage. Acinetobacter baumannii is an emerging opportunistic pathogen able to quickly acquire antibiotic resistances and survive desiccation better than other bacteria. Remarkably, A. baumannii does not have a LexA homologue and as a result, there is much to learn about the A. baumannii gene network in response to DNA damage and environmental stress. Clearly, A. baumannii is adept at surviving harsh environments, and we have previously shown that A. baumannii acquires antibiotic resistances due to activities controlled by the DNA damage response (DDR).Moreover, we have evidence suggesting that there are multiple regulators involved in the induction of the A. baumannii DDR and that there are multiple layers involved in its regulation. In this work, we have identified a DDR regulator of error prone DNA polymerases, the DDR‐regulated activities responsible for cellular mutagenesis. Through a forward genetic screen, we have found that when a TetR‐like protein is inactivated, there is deregulation of the expression of several genes that encode error‐prone DNA polymerases and of another previously identified transcription factor, UmuDAb. Here, we refer to the TetR‐like regulator as EppR (Error Prone DNA Polymerase Regulator), and we show that it binds to the promoter region of several genes encoding error‐prone polymerases and that it represses their expression. Our data is consistent with EppR playing a role in the A. baumannii DDR as a repressor of expression of error‐prone DNA polymerases.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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