Giving antibiotics a boost

There’s no sugarcoating it: The growing ability of harmful bacteria to resist our antibiotics could develop into a serious crisis. Rampant overuse of antibiotics and other antimicrobial medicines by doctors, veterinarians and even operators of agricultural feedlots has backfired, generating strains of “superbug” microbes that can survive our entire arsenal of drugs. This is the problem Dr. Luca Guardabassi has set out to solve, and he’s doing it in a way that he hopes will serve as a new weapon in the seemingly endless battle between drug developers and the superbugs that inevitably evolve defenses against each new pill we throw at them.

Instead of taking the usual path and focusing on creating new antimicrobial medicines, the Italian microbiologist — who splits his time between research positions in Copenhagen and the West Indies — has a different idea. Guardabassi is trying to bolster existing medicines by developing so-called “helper drugs” that weaken drug-resistant microbes, making them easier prey for existing antibiotics.

“Superbugs are not insensitive to the antibiotics they are resistant to,” says Guardabassi, explaining that if we can just crack through these bacteria’s defenses, the antibiotics can still do their jobs.

The idea of bolstering antibiotics has been around for years, but they weren’t called helper drugs — a term Guardabassi came up with. “It’s kind of a sexy term to reconfigure drug development,” says Dr. Keith Poulson, a bovine veterinarian at the University of Wisconsin who studies microbial infection. He gave the example of the antibiotic amoxicillin, which later had an acid named clavulanate added to it to expand its reach and target anaerobic bacteria that developed resistance to the original drug.

What hasn’t been done before is the way Guardabassi finds vulnerabilities to target with his helper drugs. In his lab, he sequences the genetic makeup of drug-resistant bacteria and identifies which genes are necessary for each bacterium’s method of resistance. Once he knows that, he develops helper drugs that go in and shut those genes off. It’s the same idea as adding clavulanate to amoxicillin, says Poulson, but no one else has tried to alter or disable specific bacterial genes.

If Guardabassi’s work does eventually lead to a breakthrough in the struggle against antimicrobial resistance, the world can thank one of his ex-girlfriends for it. Born into a family of veterinarians, Guardabassi originally planned on following in their footsteps. But while he was studying to become a veterinarian at the University of Pisa, he spent some time in Spain and met a woman — whose name Guardabassi didn’t share over our Skype call — who he followed to Denmark. Once he got there, he learned that he would need to speak fluent Danish to practice as a vet. So he switched gears, applied for research grants and began work on his Ph.D. While that romance didn’t stand the test of time, his passion for studying antimicrobial resistance did.

“The week I got notified of the grants, I split with this girl,” he told me over Skype, chuckling over his dramatic entry into research. “I decided to do the Ph.D. Looking back, I think it was a good choice.”

While the research surrounding antimicrobial resistance is broad and encompasses many different fields of science, the stakes are also very high. Just this past January, a Nevada woman died because she was infected with a bacteria that resisted treatment by every available antibiotic — even the carbapenems, which are regarded as “antibiotics of last resort.” Antibiotic-resistant superbugs are also common in animal feedlots, infecting many of the farm animals we eventually eat for dinner, which spreads disease resistance far and wide.

What’s especially frustrating is the seeming inevitability of it all. When you eradicate a bacterial infection with an antibiotic drug, most of the bacteria die. But if even a few cells of bacteria contain genetic traits that allow them to survive the drug, they can reproduce and proliferate. Thanks to the same evolutionary processes that enabled life to adapt and change over time, the next generations of that bacterial strain now carry those same resistance genes. It’s sort of like how you only get chicken pox once because your immune system learns how to fight it off after the first time. But this time, it’s the disease that learns to fight back.

The typical solution to this problem is to try and develop a new class of antibiotic. This is the sort of discovery that would bring fame to the scientists and fortune to the pharmaceutical companies that pulled it off. But their success would be short-lived: There would be some bacteria, just like before, that develop resistance. We would find ourselves back at square one — thanks a lot, Darwin.

That’s why Guardabassi and his team from the University of Copenhagen Center for Control of Antibiotic Resistance are taking a different approach by developing their helper drugs. If a bacterial cell is a medieval castle under siege, then antibiotics can be seen as a surrounding army trying to breach the perimeter and burn the castle to the ground. In this scenario, it’s still the antibiotics that do all the dirty work — Guardabassi’s helper drugs just provide them with a battering ram so they can break down the front gate.

His ultimate goal is to not only make antibiotic drugs more effective but to make it possible for doctors to prescribe lower doses, which would slow the development of new resistant strains. This is the focus of Poulson’s research at Wisconsin, too. He conducts susceptibility screenings on samples sent in from dairy farms around the country, though most are from nearby farmers. The data from his surveys reveal which strains of bacteria can resist which drugs so he can give clinical recommendations to farmers and veterinarians. He says lately he’s been seeing a larger number of strains that can resist multiple drugs, most likely because resistance evolves over time.

“…we found that changes in use either by discontinuation of a drug or more appropriate use decreases resistance, which makes intuitive sense,” says Poulson, though so far, his findings are correlative.

Guardabassi focuses his work on bacteria that are important health threats. He’s worked on helper drugs for Klebsiella pneumoniae, a bacterium that can cause bloodstream infections and meningitis, as well as harmful strains of E. coli that lead to serious intestinal diseases.

His elegant approach to weakening drug-resistant bacteria — first sequencing their genetic structure, then finding out which genes are keeping the antibiotics from working, and finally developing a helper drug that will turn them off — could help slow the spread of infections not only in food animals but in people as well.

For example, in cases where antibiotic-resistant cells physically prevent antibiotic medicines from entering and wreaking havoc, Guardabassi has developed a way to turn off the genes necessary for strong bacterial cell walls, weakening the cells’ outermost defenses. More recently, Guardabassi’s research suggests that he figured out how to turn off some of the genes that are directly responsible for fighting off the antibiotic.

He has contacted a number of pharmaceutical companies that are reviewing his work and, according to Guardabassi, have expressed interest.

These developments are much needed. Poulson says that his lab recently discovered a new mechanism by which Salmonella bacteria — one of the most common causes of food poisoning — spread antimicrobial resistance. He and his colleagues learned that in Salmonella, the instructions for fighting antibiotics are contained in plasmids rather than chromosomes, so it can be shared among bacteria without needing to wait for the resistant bacterium to multiply and spread.

Guardabassi now conducts much of his research in an unlikely setting: the balmy Caribbean island of Dominica, home of Ross University. When he’s in Europe, he spends at least part of his time teaching veterinarians how to better manage antibiotic use both in medical practice and on farms. But in the West Indies, that’s not the best use of his time. “Here on the island there are four or five veterinarians practicing, so I don’t have much to teach here,” he says. Instead, he focuses on developing those helper drugs, confident that his labors will eventually lead to a whole new way to confront antimicrobial resistance.

“There is a long way to get there, but I am determined to use the rest of my career to accomplish this goal,” Guardabassi wrote in an email, saying he hopes to begin collaborating with a pharmaceutical firm soon. “I think if you have a good idea that can solve problems, you can find someone interested in it,” he says. “I’m optimistic by nature.”