For the last few decades, syphilis has been re-emerging around the world. This may seem surprising; it can be treated successfully with antibiotics, after all. Yet, amid failures in public health campaigns and the challenge of fighting a disease that can sometimes spread undetected, syphilis is making its comeback. Estimates suggest that there were 10.6 million cases worldwide in 2008. And with its reemergence, it brings a new weapon: drug resistance.

For Natasha Arora, a population geneticist, the reemergence was intriguing. Although she started out studying orangutans, the tools of population genetics are multi-purpose, and she took a sideways step into researching syphilis instead. By studying syphilis samples taken from patients around the world, Arora and a team of researchers have found that one of the two modern groups of syphilis is far more widespread than previously thought and that both current strains show resistance to second-line antibiotics called macrolides.

Penicillin is the first choice to treat syphilis, but sometimes macrolides are prescribed instead. “Penicillin needs to be given intramuscularly (for early syphilis) or intravenously (for late syphilis)," says Lola Stamm, an epidemiologist at the University of North Carolina, who collaborates with Arora but wasn’t an author on this paper. "This can be a problem in developing countries, and most people don’t like needles.”

Macrolides—including a widely used drug called azithromycin—can be taken orally, making them much more convenient. That convenience, alongside other factors like penicillin allergies, has increased the use of macrolides.

Azithromycin is also used for a range of other sexually transmitted diseases, says Arora. Since people can be infected with syphilis without knowing it, this means that a prescription of azithromycin can unwittingly be given to someone who has syphilis, contributing to the development of resistance.

Researchers studying syphilis have been aware of a growing problem with macrolide resistance, says Stamm. “At first, the macrolide treatment failures were in US patients, but then there were reports of macrolide treatment failures in patients in several other countries.” Macrolide resistance is now a “global public health problem,” she says.

But researchers haven’t known how widespread this resistance is, because a lot of research has been done on strains of syphilis that were obtained from humans (sometimes a long time ago) and then kept in labs, passed down in generations of lab animals. The information from these strains is useful, but it doesn’t tell us much about what strains might be prevalent in the real world or how they might have evolved differently from the strains in lab animals.

Arora’s team gathered samples from patients with syphilis (as well as related diseases called yaws and bejel) from 12 different countries, representing the Americas, Europe, Africa, and Australasia. They compared the genomes of the samples and used them to construct an evolutionary history of the disease.

They found that the two current clades (categories) of syphilis infections had a common ancestor in approximately the 18th century. One of these clades, called SS14, has a particular strain (SS14-Ω) that seems to have split from the others sometime in the middle of the twentieth century. Syphilis research has largely focused on the Nichols strain, but SS14-Ω was actually more common in their samples. “We didn’t expect to see something so widespread,” says Arora. “We expected regional clusters, maybe, but instead we see something that apparently has crossed frontiers and boundaries.”

It’s not clear why SS14-Ω is so successful. There could be a biological explanation, like it having an increased transmission rate, says Arora. But it could also be social or demographic reasons: “Perhaps there’s a strain type that circulates among networks of people more easily.”

Isolates of both strains show up with resistance to azithromycin, but resistance is far more prevalent in SS14. A quarter of the Nichols samples had the genetic pattern that leads to macrolide resistance, but 90 percent of the SS14 samples had it. Together, this evidence suggests that SS14-Ω is a relatively new strain of syphilis that’s far more widespread than we thought and far more resistant to macrolides than we thought.

It’s an alarming discovery, but rather than panic, it's cause for concerted research efforts and careful prescription practices. “Physicians need to be extremely wary about using macrolide drugs to treat syphilis,” says Stamm. Arora points out that syphilis isn’t resistant to multiple kinds of antibiotics yet, but that could be something that evolves in the future. It’s important to continue observing the syphilis genome to spot early signs of this, she says.

Arora's team is now working on finding a set of genes that people can easily sequence to understand local patterns in syphilis, she says: "We need a few genes that would quickly help doctors and clinicians find out what’s going on, what strain type am I looking at, and how much resistance there is.” This data, along with samples from a broader range of countries and hard-to-reach places, would make it possible to understand the disease and its patterns much better.

Nature Microbiology, 2016. DOI: 10.1038/NMICROBIOL.2016.245 (About DOIs).

Editor's Note: This post has been updated to correct Stamm's connection with the study authors; to clarify Arora's statement on a possible biological explanation for SS14-Ω successful spread; and to correct that there are two modern clades of syphilis, not two strains.