Researcher Explains Challenges in Finding Novel Antibiotics

The last time scientists discovered a novel class of antibiotics that would eventually make it to market was in 1984. That drug, daptomycin, was approved by the Food and Drug Administration in 2003, nearly two decades after its discovery—and Richard Baltz was one of the researchers who helped develop the promising molecule into an FDA-approved drug.

Because bacteria that are resistant to one antibiotic often develop resistance to similar drugs, novel classes of antibiotics are critically needed to stay ahead of antibiotic-resistant bacteria, also known as superbugs. Unfortunately, only about 25% of the antibiotics in clinical development represent new classes of antibiotics, and none of them have even the potential to work against the most dangerous superbugs.

Baltz spoke recently about his experience developing daptomycin, including the challenges associated with discovering and developing new antibiotics, and what needs to happen to address what is now a more than 35-year drought in antibiotic discovery.

This interview has been edited for clarity and length.

Q: Can you talk a little bit about your background? What drew you to study antibiotic resistance and infectious disease?

A: Well, after getting my undergraduate degree in microbiology at The Ohio State University, my notion was that I would go to medical school. But I wanted to get some real-world experience first, so I took a job at Eli Lilly and Co., which at the time was a top global company for developing antibiotics, and I got the opportunity to work on antibiotic fermentation for developing a category of drugs called cephalosporins.

That experience changed the trajectory of my career. About a year into my time at Lilly, I decided to go to graduate school instead of medical school, and I pursued a Ph.D. in microbiology from the University of Illinois at Champaign-Urbana. I got to do a lot of leading-edge research during my time there, and that solidified my decision to pursue molecular genetics as a career.

After I finished my Ph.D. and postdoctoral research, Eli Lilly offered me a position to develop a molecular genetics program to augment its fermentation strain improvement programs. Later, the company asked me to create and head a new molecular genetics department to develop recombinant DNA technologies for antibiotics and human proteins.

Q: When did you start working on daptomycin?

A: I started working on the drug that would ultimately become daptomycin in the late 1980s. We were already seeing bacteria develop resistance to vancomycin, an antibiotic that Eli Lilly produced, and so there was interest in developing new antibiotics that could treat emerging resistant pathogens such as Staphylococcus aureus. But Eli Lilly discontinued clinical development of daptomycin in the early 1990s because early clinical studies showed some muscle toxicity associated with the drug.

That was the beginning of the end of Eli Lilly’s work on antibiotic development, and I retired from the company a few years later.

Then, in an interesting turn of events, Cubist Pharmaceuticals licensed daptomycin from Eli Lilly and began to work on clinical development of the drug. A friend of mine, Frank Tally, was leading the effort at Cubist, and I joined the company in 1998 as a consultant, then became an employee in 2001 to lead the natural products program. The rest, as they say, is history: Cubist took a molecule that had been discarded due to safety concerns, figured out a way to overcome the toxicity issues, and made it work.

Q: That’s quite an odyssey.

A: I can’t tell you how rewarding it was when daptomycin was ultimately approved as a new antibiotic, after I’d worked on it in different capacities for about 15 years. It’s a pretty amazing story, really—one that should give us all some hope.

Q: We could use that hope, considering that it’s been more than 35 years since the last novel antibiotic class was discovered, and almost 20 years since daptomycin was FDA-approved. What challenges did you face in the development of daptomycin, and how they are relevant to today’s antibiotics discovery and development efforts?

A: A lot of the challenges we faced are not unique; they’re challenges faced by most antibiotic developers. First you have to find a molecule with antibacterial properties. We don’t even know how many molecules are out there, and it can be hard to know where to look. In the case of daptomycin, it was a soil sample from halfway across the world, on Mount Ararat, that contained the daptomycin-producing microorganism Streptomyces roseosporus.

During what we now think of as the golden age of antibiotic discovery, 50 years or so ago, new and promising molecules were fairly prevalent and easy to find. Today, it’s much harder to collect samples from around the world, and finding molecules that are new and different from what we already have has become much, much harder. Instead, scientists are investing significant time, energy, and money only to rediscover the same molecules.

And even when you find a promising molecule, it takes a lot of time to improve it to optimize both its antibacterial activity and its safety: You have to be mindful of toxicity concerns, such as we initially had with daptomycin. You can have a product that’s outstanding at killing bacteria, but that doesn’t do you any good if it’s also killing the human with the bacterial infection. From a soil sample to the point where a compound is ready to be safely mass-produced as a drug can take years, even decades.

That takes resources.

Contrast these challenges to a drug with a comparatively simple chemical compound, such as—for example—a selective serotonin reuptake inhibitor to treat depression. That kind of drug is far easier and cheaper to make, and a patient could potentially need to take it for life, leading to much higher revenues than for an antibiotic that’s typically taken for short periods of time. It becomes clear pretty quickly that there are far more financially attractive therapeutics for drug manufacturers than antibiotics.

Additionally, we don’t have the human expertise or the infrastructure of big pharmaceutical companies working on antibiotic discovery in the way we did decades ago. Most of the folks who worked on antibiotics that derive from natural products are now retired or dead.

Q: So what needs to happen to change this dynamic—to give the world hope, to use that word again, in the quest for the new antibiotics we so urgently need?

A: We need new approaches that provide orders-of-magnitude improvements in terms of speed and efficiency of drug discovery. For example, can we leverage bacterial genome sequencing technologies, which have become quicker and cheaper to use over the past decades, to allow researchers to rapidly scan whole genomes, compare the encoded gene clusters to what’s already known, and quickly identify potential new antibiotic gene clusters? Advances like that would save time and resources and be a game-changer.

Q: Do you think the average nonscientist understands why we need new antibiotics?

A: I think a lot of people are aware of antibiotic-resistant bacteria, the superbugs, but they assume that this problem won’t affect them. It’s the “it’s not going to get me” mentality. We’re seeing a similar phenomenon with COVID-19; no one really plans to end up in an ICU. When it comes to superbugs, we need to find a way to shake people out of their complacency, communicate what’s really at stake, and act accordingly.

Q: You mention COVID-19. Are there lessons we can learn from the pandemic as we work to prevent another public health crisis with antibiotic resistance?

A: I think one of the major lessons is that progress is possible when something becomes a global priority in the way that COVID-19 has. Companies and governments collaborate. They share information. And they compete to deliver the best solutions. That’s how we need to think about antibiotic resistance, and we need to do it now. We’re doing ourselves a grave disservice if we wait to take action until we run out of antibiotics—because we’re getting pretty close to that already.