Zinc Inhibits Plasmid Transfer in Gut Microbes

Genes responsible for antimicrobial resistance (AMR) can spread from microbe to microbe through circular genetic material called plasmids, and this lateral transfer occurs in the gut. This week in Applied and Environmental Microbiology, researchers in Iowa report that the transmission of some AMR plasmids may be inhibited by a readily available source-;dietary zinc supplements.

"This is the first time where we've discovered that zinc inhibits the process of plasmid transfer, and at lower concentrations it has minimal effect on bacteria" said microbiologist and senior author on the study Melha Mellata, Ph.D., at Iowa State University. That's important, she said, because killing gut bacteria might disrupt the microbiome, which could have downstream ill effects on a person's health.

But if we just prevent the plasmid transfer, then we can reduce the spread of antimicrobial resistance."

Melha Mellata, Iowa State University

AMR infections are a growing problem. Millions of people are diagnosed with AMR infections every year and 35,000 people die from them, according to the Centers for Disease Control and Prevention. When bacteria transfer AMR genes, Mellata said, they often transfer resistance to multiple drugs, which means that a person might have a resistant infection even before they receive antibiotics. Stopping the transfer of plasmids could help slow the spread of AMR genes.

Researchers in Mellata's lab have been investigating how gut microbiome health relates to overall health. In a recent study, however, they found that when both probiotics and a live Salmonella vaccine were given orally to chickens, the Enterobacteriaceae bacteria in the animal gut had fewer plasmids. That observation, Mellata said, prompted them to consider testing other oral treatments to inhibit plasmid transfer. 

Logan Ott, a researcher in Mellata's lab, led the work on the study. He and a team of undergraduates collected readily available supplements to test their potential ability to inhibit plasmid transfer. They dissolved the products in test solution, then ran hundreds of reactions in which avian pathogenic Escherichia coli containing a multi-drug resistant plasmid conjugated with a plasmid-free human E. coli isolate.

They found a sharp drop in plasmid transmission in bacterial strains supplemented with zinc, compared to bacterial strains without zinc. In addition, higher doses of zinc correlated to lower levels of plasmid transmission. Those observations were promising, Ott said, but also a little mysterious. Previous studies had observed that heavy metals could induce the conjugation process that resulted in plasmid transfer. The group then used qPCR to take a closer look at how the zinc affected the process at the level of genes.

"We found some pretty unique mechanisms on how zinc might actually be inducing this inhibition when previous literature would state that we should expect more," Ott said. Their analysis showed that the zinc induced overexpression of replication genes-;so much so that it likely overloaded and inhibited the process. They also found that while zinc did seem to promote the genes responsible for conjugation, the mineral inhibited specific proteins required to build the bacterial structures used in conjugation. As a result, the overall process of transmission was stymied.

The next steps, Mellata said, include testing the transfer of plasmids with other AMR genes and experimenting with animal models to see if the lab results also hold in vivo. Ott noted that scientists' understanding of how bacteria interact and share genes in the gut is poorly understood, and future studies could help elucidate some of those mechanisms.

Mellata is particularly encouraged that such an inexpensive, readily available supplement-;zinc-;may play a role in addressing an emerging threat. "Sometimes the solution can be just to use the old stuff we already have in our closet," she said. "We just have to make the effort to test it."