How Does Topoisomerase I Differ from a Quinolone Antibacterial?

Kirk Hevener, PharmD, PhD, assistant professor of Biomedical and Pharmaceutical Sciences at Idaho State University, College of Pharmacy, explains the differences between topoisomerase I and quinolone antibacterials.

Interview Transcript (slightly modified for readability)

“We’re looking at two narrow-spectrum drug targets right now in my laboratory; the first is an enzyme called FabK, which is specific to the bacteria Clostridium difficile. The second is a DNA active protein called topoisomerase I in Streptococcus; now that’s specific to the entire genus of Streptococcus, but we’re looking at Streptococcus mutans, which is an oral pathogen that’s also been associated with certain blood and heart infections.

The quinolone antibacterials are broad-spectrum agents that target what we call type II topoisomerases. The topoisomerase enzymes unwind DNA. As DNA is replicated by polymerases or copied, it supercoils, and the topoisomerases are responsible for relaxing the supercoils, and there are some other [enzymes] that are responsible for re-coiling it. There [are] two types of topoisomerases: those that cut both strands of the DNA, and then pass another through and reconnect; and the type ones, they normally cut one strand of DNA, pass through, and reconnect. The quinolones target the type II topoisomerases.

There are no antibacterial drugs on that market that target the type I bacterial topoisomerases, so my laboratory is looking at those. The reason that we think that it could be a narrow-spectrum or a selective antibacterial target, is because there’s two type I topoisomerases and we call those: topoisomerase I and topoisomerase III. All bacteria have topoisomerase I, most bacteria also have III, and they have an overlapping role. So, if you were to try to knock out topoisomerase I from bacteria that also had topo III, you could do it, because topo III can continue to do the job, but you can’t knock it out from an organism that only has topo I.

The hypothesis here, that we’re working on and that we’re presenting some preliminary data [on] today, is that organisms that only express topoisomerase I, as opposed to those that have both topo I and topo III, will be differentially susceptible to the inhibition of topoisomerase I. Essentially our hypothesis is, that you’ll see a selective, or narrow spectrum activity if you can selectively target topoisomerase I in bacteria like the Streptococci that only have topo I.”