Antimicrobial resistance is a One health problem requiring action on multiple fronts. It’s not just about reducing antibiotics in a clinical setting, other sectors and every individual or potential antibiotic consumer needs to chip in. However, a smart way to create immediate gains could be that we target the most commonly used antibiotic in the world. Yet, up until a few weeks ago I hadn’t even heard of this antibiotic despite actively working on the topic of antimicrobial resistance for the past 7 years. You could walk into a pharmacy, medical center or hospital but surprisingly, you won’t find that antibiotic there. Some antibiotics are only for veterinary use but even there you won’t find it, nor has it any use. There are so many other places and processes in which antibiotics are used but the most commonly used antibiotic has no role in any of those. Despite this, approximately 1.35 million metric tons of this antibiotic is used every year. That’s more than 10x the amount of antibiotics consumed in a year for human and veterinary purposes combined. Try and think about that for a moment: what potential consequences could this unwillingly have  on our environment, microbial diversity and so many other aspects of our day-to-day live? Mind boggling… it’s the only thing that comes to mind.

So where do we find this antibiotic? Well, it’s almost everywhere around us. It’s likely in or on some of the fresh food in your fridge. Not as a preservative but a contaminant. You see, it’s primary use is in agriculture. Not as antibiotic but as herbicide named glyphosate. Some of you may know already that glyphosate, branded as the herbicide ‘roundup’, acts as antibiotic but I was completely ignorant about this fact. So how does something designed to kill weeds also kills microbes? How come it took so long to figure out that glyphosate has antibiotic properties and what are the consequences of that ‘ignorance’ we had.  Let’s explore all of these aspects together and let’s look at this topic from a different perspective.

The Shikimate Pathway: Glyphosate’s Key to Abundance and Antibiotic Action

Glyphosate is a broad-spectrum herbicide. It acts on an enzyme called 5-enolpyruvylshikimate-3-phosphate synthase crucial for the synthesis of aromatic amino acids (the Lego blocks of live). Without those aromatic amino acids, the plants can’t grow and they will die making glyphosate an ideal herbicide. This is particularly of interest when the main crop being grown is genetically modified (GMO) to be resistant to glyphosate. A true case of 1 + 1 = 3 ; the combined use of GMO crops with glyphosate has led to drastic increases in crop yield resulting in today’s underappreciated abundance of food in most developed countries.

The ‘shikimate’ pathway targeted by glyphosate is of clinical relevance as well. Antiviral medicines like oseltamivir are a byproduct of the shikimate pathway in certain plants like star anise. Where things get tricky, which wasn’t originally known, is that many bacteria and fungi rely on the shikimate pathway as well (although not exclusively). Yet, at certain concentrations, glyphosate’s action on the shikimate pathway in bacteria will limit bacterial growth and eventually kill the bacteria. Consequently, glyphosate emerged as an unknown antibiotic and was patented for these properties in 2010.

Let’s reimagine our previous statement: 1.35 million metric tons of an antibiotic is used on agriculture land every year. It ends up in the soil, water supplies and the overall environment. The breeding ground of microbial communities exposed to yearly acid rains, that surely must leave a mark. But it also comes with a rain of abundant food supply to humans, surely that can be a bad thing! At first glance, maybe not directly to humans as the shikimate pathway is only present in plants and microbes. However, it’s not just about us and we need to continue this story on a microscopic scale.

Beneath our Feet: Glyphosate’s Grip on Soil Microbes and Ecosystem Balance

The soil we walk on is a thriving community of different microbial species, some more dependent on the shikimate pathway than others. One can imagine that using glyphosate would reduce the overall microbial diversity in soil through selective pressure. This is what has been observed so far: reduced microbial diversity, an overall increase in gram-negative bacteria and reductions in acidobacteria upon glyphosate soil exposure. Those changes may not persist over time, no need to care about this right? Not exactly, disruption persists when glyphosate exposure persists and that reduced microbial diversity,  it can impact the nutrient recycling and diseases suppression processes normally present in soil. To add even more complexity, some bacteria can actually metabolize glyphosate. This intrinsic competitive advantage over other microbial species further contributes to soil microbial dysfunction and imbalance. It’s not just bacteria either, fungi are equally impacted causing further deterioration of microbial communities.

Reduced microbial diversity and community structure, what does this actually mean? In a way, it’s very similar to how team dynamics work for humans. Chemistry and teamwork are known drivers to success and having an unbalanced team usually means that the work doesn’t get done properly. The same is true for the microscopic world: microbes communicate and collaborate with one another supporting the larger macroscopic world we observe. Reduce that team chemistry in soil microbial communities and the actual chemistry of the soil will change: reduced diversity impacts soil pH as well as other physicochemical properties. Luckily, nature always has a method to restore balance and create harmony. Reduced microbial diversity tends to normalize upon removal (or natural degradation) of glyphosate. It only takes time. The challenge: the same soil used for agriculture today will get exposed again in a year, in 2 years, … over and over again. At the same time, we are using more and higher concentrations of glyphosate. Thus, the risk of sustained soil dysfunction is not farfetched. Furthermore, agriculture practices have changed. Pre-harvest desiccation was introduced where glyphosate use prior to harvesting aids with uniform crop maturation and drying of crops for easier harvest. And so, the risk cycle continues.

Changed microbial composition, changed soil properties and sustained excessive glyphosate use. Not surprisingly, plants and microbes have learned to develop resistance against glyphosate. All of a sudden, glyphosate sounds more and more like the other antibiotics that I deal with on a daily basis.

From Hospitals to Harvests: The Unseen Connection between Antibiotic and Glyphosate Resistance

If we take a side step to antibiotic use in a healthcare setting, we know that excessive use of antibiotics is associated with emergence and spread of antibiotic resistance mechanisms. As glyphosate is an antibiotic, one would expect that excessive use of glyphosate would result in emergence and spread of glyphosate resistance. The reality is that this has already happened. Beside the glyphosate resistant engineered crops, other weeds and plants have developed natural resistance to glyphosate. In fact, multiple mechanism of resistance have emerged. For example, one mechanism of resistance is ‘target site mutations’; a process by which the normal binding of glyphosate to the plant target enzyme is disrupted. An alternative method is gene amplification of the enzyme targeted by glyphosate. Consequently, plant cells create multiple copies of that gene on circular extrachromosomal DNA to avoid complete metabolic disruption. Glyphosate absorption and translocation can also be reduced, effectively keeping glyphosate away from its target enzyme through energy-dependent processes. Now for someone working in the space of antimicrobial resistance this might trigger an odd sense of familiarity. And it should. Bacteria have developed resistance to many antibiotics used for treating infections through strikingly similar mechanisms.

One may argue that this all of this is not relevant to humans. Glyphosate is not used as an antibiotic to treat human diseases. True. Nevertheless, we can’t state it doesn’t impact us either as some evidence suggests that glyphosate increases the prevalence of existing antibiotic resistance genes and mobile genetic elements in clinically relevant bacterial species. Whatever the case might be, one thing is clear: there are striking similarities between glyphosate and antibiotics. Excessive use of either leads to resistance development. Also, the similar biological mechanisms in plants and bacteria driving resistance reveal nature’s elegance of not reinventing the wheel.

The Glyphosate Conundrum: Feeding Humanity at what Cost?

At this point in time, we know what glyphosate is. It is likely leaving a mark on our environment and resistance to glyphosate is developing quickly. Even if glyphosate would not be considered an antibiotic, the striking resembles of humanity’s experience with glyphosate and antibiotics is remarkable. Both inventions were a game-changer for their respective field and have resulted in massive benefit for humanity. At the same time, for both we didn’t fully understood the consequences of what excessive use would lead to. Innovations without any negative consequences, only time would show us otherwise. Even when the evidence starts to demonstrate we might need to change our way of thinking, we tend to ignore at first. Change is challenging. In case of glyphosate, the challenge is significant. If it does indeed impact human health, we would need to step away from something that helped humanity create a guaranteed high yield food supply. Are we ready to take that challenge head-on?

Regardless, the million dollar question remains unanswered: does glyphosate impact human health? For the moment, I don’t have an answer. But I will be exploring this topic and relevant perspectives in a separate article in a few weeks from now. Stay tuned!