Quinolone mechanism of action: sensitivity, mutagenesis and tolerance
Agarwal, Saloni Jain
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Antibiotics are a foundation of modern medicine, helping to save millions of lives since their discovery in 1928. But the improper and excessive use of these drugs over the last few decades has led to an alarming increase in antimicrobial resistance; coupled with the recent decrease in antibiotic discovery, it is widely thought that we are approaching a post-antibiotic era. A less well-understood problem is that of drug tolerance. Even at high doses, antibiotics often cannot kill all the bacteria in an infection because of cells that are able to tolerate antibiotic treatment. Evidence points to drug-tolerant cells, also called persisters, to be a major cause of treatment failure and chronic and recurring infections It is imperative that we develop insight and methods to prevent the spread of antimicrobial resistance and combat antimicrobial tolerance. One key effort is characterizing bacterial responses to antibiotic drug treatment to generate a more comprehensive understanding of the factors that contribute to cell death and to elucidate potential targets for new therapies. Quinolones are an important class of antibiotics that target DNA replication. They bind to topoisomerase II and IV, leading to eventual DNA fragmentation and death. However, the precise mechanism by which they work is not well understood. Because they inhibit DNA replication, quinolones lead to up-regulation of the SOS response, which allows for increased mutagenesis and the potential for increased antimicrobial resistance, thus making quinolones an interesting class of antibiotics to study. Although quinolones are one of the most effective classes of antibiotics, there are many conditions in which they do not kill, such as in stationary-phase cultures. Understanding the mechanism behind quinolone killing, quinolone-induced mutagenesis and tolerance to quinolones is important to improve quinolone efficacy. Here I have presented my work on understanding quinolones: sensitivity, mutagenesis and tolerance. In understanding quinolone sensitivity, I focus on DNA repair and its involvement in quinolone-mediated death. I then probe the field of stress-induced mutagenesis by quinolones, uncovering phenotypes of dose-dependent mutagenesis that have previously been uncharacterized. Finally, I focus on drug tolerance and how density-dependent tolerance to quinolones can be reversed by up-regulating cellular respiration through the addition of a carbon source and electron acceptor.