Fluoroquinolone Herbicides

Introduction

Over the years I have outlined several times how the quinolones (fluoroquinolones) will be part of our society for many years to come, for several reasons. This article reveals another area of expansion. 

In the publication, Nonclassical Biological Activities of Quinolone Derivatives published in Journal of Pharmacy & Pharmaceutical Sciences Vol 15, No 1 2012, it outlines why the quinolones are an excellent platform (scaffold) for modification to create new pharmaceutical products.

The Journal states “Quinolones as “privileged building blocks” with simple and flexible synthetic routes allow the production of large libraries of bioactive molecules. Because of their diversity, drug-like properties and similarities to specific targets, they are considered a central scaffold to build chemical libraries with promising bioactivity potential.”

The quinolones are very effective at what they do….kill. 

Because of this, I alerted my readers to watch for development in three areas:

Antibacterial

Anti-cancer

Antiviral

Well now you can add a fourth area to the development:

Herbicides

Fluoroquinolone Herbicides

Recently, while I was lying in bed winding down getting ready to go to sleep, I was thinking about an article I recently read how scientists are trying to re-purpose fluoroquinolones as herbicides. The article “Antibiotic analogue puts researchers on path to ending herbicide drought” was published in 2018 and it really didn’t garner much attention at the time.

In a nutshell, some mad scientists in Australia and the United Kingdom have found a new herbicidal mode of action by modifying the antibiotic ciprofloxacin.  Finding a new herbicidal mode of action has evaded scientists for 20 years.

Like kids with an erector set, scientists have been tinkering with the fluoroquinolone scaffold and found a ciprofloxacin analogue that selectively targets an enzyme required for plant growth yet has decreased antibacterial activity.

Joshua Mylne and Keith Stubbs, from the University of Western Australia, and their colleagues, target DNA gyrase in their new system. In their literature they state that DNA gyrase is a type of enzyme that helps control DNA unwinding during replication. “It is essential for plant growth but not present in humans, and therefore a prime herbicidal target.”

DNA gyrase not present in humans?  Well maybe, but you would think that researchers would delve deeper in the complete profile of the drug they are tinkering with, wouldn’t you?

As far back as 1993, research showed that Ciprofloxacin targeted DNA gyrase AND toposiomerase II (1).  DNA gyrase is the prokaryotic equivalent of DNA topoisomerase II. 

Anyway, I digress.  Why would we need newer herbicides when we have the world’s most (in)famous herbicide, glyphosate?

Glyphosate Replacement?

Peter Andreana, an expert in small molecule synthesis and drug design from the University of Toledo Ohio, who was not involved in this study said that, “glyphosate is now susceptible to resistance in many different plants, so there is a substantial amount of concern.” Andreana is concerned that we need to come up with viable alternatives to replace glyphosate.

We have literally drenched the world in glyphosate and now nature is fighting back by naturally selecting plants that are glyphosate resistant.  This usually happens when humans over do it and scientists, unfortunately, appear to be search for replacements in all the wrong places. 

Concerns About Developing Herbicides from Antibiotics

Since ciprofloxacin is an antibiotic and using it directly in agriculture would greatly contribute to the ever-growing antibiotic resistance problems facing the world, the team (Mylne, Stubbs and colleagues) decided to develop analogues of ciprofloxacin with reduced antibacterial activity.

In chemistry, an analogue is a compound with a molecular structure closely similar to that of another.

To do this, they produced a basic fluoroquinolone scaffold then added chemical moieties differing in size, shape and hydrophobicity at the N-1 and C-7 positions. After some experimentation they found an analogue with sufficiently decreased antibacterial properties and increased herbicidal properties.  This confirmed to the researchers that targeting the pant’s DNA gyrase was a realistic new mode of action for herbicides.

What Could Possibly Go Wrong?

Despite the reduced antibiotic abilities of the new fluoroquinolone compounds, some scientists are still concerned about the idea of modifying antibiotics for use in agriculture, and the precedent that this will set for future research.

Jack Heinemann, an expert in antibiotic resistance and genetic engineering at the University of Canterbury, New Zealand says, “we are pushing both our medical and food systems to such extremes that we have to threaten one to temporarily relieve stress on the other.”  He feels that this poses a great threat to one of humankind’s greatest medical resource, our antibiotics.

Researcher Stubbs counters saying, “Our study is not saying that people should start putting ciprofloxacin directly onto their weeds … if you do that, you will be contributing to antimicrobial resistance.”  He continues, “We have shown that this [inhibition of plant DNA gyrase] is possible, which is really cool, but huge amounts of work will be necessary to achieve it completely.”

The team plan to extend their study by evaluating different types of fluoroquinolones that act in a similar manner and tweaking these structures accordingly to see if they can get similar results.

Conclusion

It has always held true that reality is often stranger than fiction.  Just like the fluoroquinolones, there are researchers and scientists who see toxic products like glyphosate as benign.   Despite being implicated in a whole host of health maladies, saturating our land, water, and food, they view glyphosate as useful product that has reached its life expectancy and needs to be replaced.  Unfortunately, instead of searching out safer alternatives, their thinking is shaped by an academic educational system that is likewise saturated with pressure from the pharmaceutical industry.  An industry that controls their every thought through textbooks, funding, and peer reviewed research.

I see herbicides as the next unfortunate step in the ever progressing evolution of the fluoroquinolones. 

You can’t make this stuff up, and with Halloween in close proximity I, tongue-in-cheek, have various titles swirling through my head; one of them is “The Antibiotic That Took Over The World.” Soon it seems, the fluoroquinolones, or their derivatives, will invade every aspect of our lives.

I close this article with my thoughts I had before drifting off to sleep. New herbicide brand names were swirling in my head, Levacide, Floxicide, ….well you get the idea.  What could possibly go wrong?

Or better yet, maybe they’ll develop a new human antibiotic based on glyphosate, or a glyphosate fluoroquinolone combination.

Needless to say, I didn’t sleep well.