Before the discovery of antibiotics, some of the oldest and most effective tools to fight bacterial infection were metals. Silver, copper and arsenic have been used since the Roman Empire to treat wounds and disinfect surfaces, and mercury remained the standard treatment for syphilis until the advent of penicillin.

Metals’ mixed success—and frequently harmful side effects—has kept them out of most modern pharmacopeias. But as bacteria grow resistant to the latest generation of antimicrobial wonder drugs, some research teams are giving metals and their effects on cells a second look. Clays are one promising frontier. They have a long history in the poultices of traditional medicine, and a recent study from the Mayo Clinic and Arizona State University found that a blue clay from Oregon may have a potent antibacterial effect against some of today’s most troubling bugs—E. coli, Salmonella, Pseudomonas—including variants resistant to antibiotics.

Clays often contain a mixture of metals, and those combinations could explain their effectiveness. Researchers had outlined possible reasons for the blue clay’s power over pathogens in a previous 2016 study in Nature Scientific Reports. The antibacterial activity of the clay may relate to its ability to release iron and aluminim, which can damage bacterial membranes, potentially allowing the iron to then cause further damage inside the bacterial cells. Only a few types of clay generate the right forms of these elements, however.

This combination also seems to work against a broad spectrum of bacteria, and it’s active against bacteria that form into a biofilm matrix—a sticky amalgam that can coat surfaces and be especially tricky to eliminate, explains Robin Patel, director of the Mayo Clinic's Infectious Diseases Research Laboratory in Rochester, Minn., the senior author of the new study. The team is now planning to evaluate the clay’s effectiveness in healing wounds in an animal model.

Additional lines of research are looking to exploit bacteria’s voracious need for iron. These focus on siderophores, molecules that bacteria secrete to scavenge iron from hemoglobin and other compounds within the body. Normally, these siderophore-iron molecules are absorbed through the bacteria membrane to be used as building blocks for bacterial growth.

Researchers at the University of California, Irvine are pursuing a strategy to prevent gut pathogens such as Salmonella from acquiring iron, thus inhibiting their growth. This approach uses immunization to coax the body to create antibodies. Because existing antibodies don’t attack siderophores, the team created a new molecule made up partly of sections resembling a conventional infectious agent and others that mimicked a particular siderophore from Salmonella.

Mice vaccinated with the conjugate produced antibodies that reduced the level of Salmonella in the animals’ gut by as much as 20,000-fold. This approach didn’t harm the overall bacterial community in the mice, and beneficial Lactobacillus bacteria expanded to fill the environmental niche that Salmonella left behind.

Other research is looking to harness the siderophore transport mechanism as a sort of Trojan horse to smuggle antibiotics into bacteria. Although several attempts to use this approach to develop a drug have failed, one may soon be ready for the clinic. Cefiderocol, developed by the Japanese pharmaceutical company Shionogi, packs the antibiotic cephalosporin, discovered in the 1940s, with an iron molecule that a bacteria’s siderophore latches on to. When the entire complex is drawn into the bacteria, it bypasses the cells defenses and kills the cell.

In results announced in October, clinical trials in 15 countries showed cefiderocol to be effective in treating multidrug-resistant urinary tract infections. Additional trials are testing its effectiveness against hospital-acquired and ventilator-associated pneumonia. In the United States, the company is seeking fast-track approval of cefiderocol by the U.S. Food and Drug Administration. If that happens, it could usher in a new era of interest in metals-based treatments.