What happens when the antibiotics that kill harmful bacteria stop working? A global emergency arises, according to the World Health Organization, which considers resistance to antimicrobial agents — including antibiotics — one of the top 10 global public health threats facing humanity.
In 2019, the U.S. Centers for Disease Control and Prevention had shown that both infections and deaths caused by antibiotic resistance were decreasing. This changed suddenly in 2020, with pandemic-related setbacks linked to, for instance, a forced shift from antimicrobial resistance tracking to COVID-19 cases tracking and an increase in antibiotic prescriptions, which furthered the pressure for resistance to spread.
W&M Assistant Professor of Chemistry Izzy Taylor and her lab aim to uncover new antibiotic strategies, inhibiting communication pathways between bacteria instead of killing them. Her research has been recently presented at a STEM “Research In Progress” symposium, part of a series of events funded by the Arts & Sciences Dean’s Office and the Provost’s Office to reduce research silos and further strengthen the W&M research ecosystem. In advance of World Antimicrobial Resistance Awareness Week, William & Mary News sat down with Taylor to understand how her research-in-progress addresses this rising global crisis.
The interview has been edited for length and clarity.
Q: How will your research in progress address antimicrobial resistance?
A: Our research focuses on Pseudomonas aeruginosa, a bacterium that is resistant to a wide variety of antibiotics and most frequently attacks immunocompromised patients in hospital settings. It is a really great model system for us to study in order to come up with antibiotics that follow non-traditional mechanisms impacting the ability of bacteria to cause an infection and make someone sick.
In the Taylor Lab, we target cell-to-cell communication, a mechanism called quorum sensing, which is really essential for Pseudomonas to infect a host and make them sick. Our whole idea behind going after this communication mechanism is that it’s not necessary for Pseudomonas to survive. And so, our thought process is that there is less drive for Pseudomonas to develop resistance mechanisms to such a drug that doesn’t impact the ability of bacteria to survive but inhibits their communication process instead.
I think the problem can be summed up by saying that we are not very creative with the antibiotics we currently have and are using in the clinic, as they follow just a handful of simple mechanisms. When they stop working and bugs become resistant, we just make slight modifications to the same drugs following the same mechanisms of basically killing cells. And so, there’s really a need for antibiotics that don’t kill bacteria, but just disarm them. That’s what we’re trying to do with Pseudomonas.
Q: Can your findings be generalized to other bacteria? How novel is this research stream?
A: Our broader research on Pseudomonas can absolutely be generalized to other bacteria, because virtually all bacterial species use quorum sensing as a communication process, each in slightly different ways.
In terms of drug development, the approach that we’re taking right now is really specific to Pseudomonas aeruginosa. So, any drug that we may come up with is not likely to work against other species of bacteria: In a way, this is a very good thing because even beneficial species of bacteria use quorum sensing, and you wouldn’t want to knock out that communication process for “good” microbes.
As we are very focused on one species of bacteria in particular, the types of antibiotics that we are trying to develop would not be broad spectrum at all: They would be very narrowly focused on Pseudomonas aeruginosa. In my mind, this is okay. This is still an area where we need effective antibiotics, because there really aren’t any available in the clinic. Also, I want to stress that it is a problem worth focusing on even if we don’t see Pseudomonas infections largely in the general population – because it really is a problem for those who are immunocompromised.
In terms of novelty, there are no antibiotics currently targeting quorum sensing, but other research groups are working on that mechanism. The project that I’ve taken here to William & Mary stems from the work I started during my postdoc in the Bassler Lab at Princeton.
Q: Why did you decide to focus on Pseudomonas aeruginosa?
A: I think this comes to why I wanted to focus on quorum sensing, and Pseudomonas is one of those poster children for quorum sensing bacterial pathogens.
For someone who loves using chemistry as a tool to decipher biology, quorum sensing is an amazing field to be in. Quorum sensing is essentially chemical language: For chemical biologists, it is really a dream to be able to get in there, play around and make new molecules inspired by the natural molecules that bacteria are using to talk to each other.
Q: How does your research interact with other disciplines?
A: Being a chemical biologist, as the name suggests, means that I interface a lot with the biology department.
On a more philosophical level, the whole idea of studying quorum sensing makes me feel a little bit like a linguist. I do feel like we are translating bacterial languages. So, I think there’s something there about behavior and language, and cross-cultural interactions that are happening amongst bacteria, that people in the humanities can see reflected in the science that we’re doing.
Q: Does your lab also include students from other disciplines? What is their motivation?
A: We have biology and chemistry majors; neuroscience majors are often asking about my research too.
I think the most obvious motivator for them is the idea that something they’re doing in the lab could translate into making a drug that could help people. We have been working on the very early stages of what we call drug discovery: We’re identifying these molecules that could potentially be turned into therapeutic agents, and I’m really excited about the results my students are getting.
But I also think they’re learning that it’s equally satisfying to figure out pieces of basic biology — that is, what is happening on a molecular level in these bacteria allowing them to talk to each other. And while we are primarily interested in developing potential drugs, we’re also always interested in putting together more and more pieces of the puzzle to actually understand, on the molecular level, what is the whole picture of quorum sensing.
Q: The 2023 AMR Awareness Week’s theme calls for cross-sectoral collaboration to preserve the effectiveness of antimicrobials. How is chemistry specifically contributing?
A: What is most exciting for me is that people are coming up with new ideas and mechanisms for antibiotics. I think one of the real problems that has led to the current resistance crisis is that we haven’t really branched outside of very traditional mechanisms for antibiotics.
Currently, I don’t think there are lot of resources, at least in the pharmaceutical industry, that are being put into developing new antibiotics with new mechanisms of action. Many academic scientists and academic chemists are really going after these other mechanisms, exploring new things that we can try and develop. And this is currently happening in academic labs, with universities being the ones stepping up and doing the basic biology research to say that this approach can be successful, and we should be devoting resources to this.
Q: Do you think that the role of antibiotics is sometimes misunderstood?
A: I am not working in a clinic, but I think there’s a general misunderstanding about what is the thing making us sick. And it really matters to ask what the root cause is because it determines what you should do about it.
Something that I have seen and heard about antibiotic regimens is that many people may not understand that, if your doctor prescribes a whole routine of antibiotics over time, you have to finish that prescription, you have to carry out those antibiotic treatments and keep going with them. Because if you stop early, perhaps because you’re feeling better, that’s when the persisting bacteria – the ones that are mutated and resistant to that antibiotic – are given an opportunity to flourish.
When you take antibiotics, you’re putting pressure on the bacteria that are staging this infection, and this kills off most of them. There are very often a few cells that undergo mutation and will survive that initial treatment. And so, if you kill off the vast majority of the cells that were there, you might start feeling better, but not finishing treatment is giving the ones that survive an opportunity to grow back and come back as superbugs.
Antonella Di Marzio, Senior Research Writer
