A collaboration that includes scientists from the Department of Energy’s (DOE) Argonne National Laboratory has discovered that the bacteria performs this feat by confining the toxic compound to the equivalent of a molecular dungeon.
The compound contains unusual properties, said Andrzej Joachimiak, an Argonne Distinguished Fellow in the Biosciences division. “For example, they can be powerful antitumor agents or they can be antibiotics. But because of their toxic properties, the question was, how do the bacteria produce this compound without being killed?”
The compound is an enediyne, which is produced by a family of soil bacteria. The bacteria, the researchers discovered, produce a protein that binds to the compound, sequestering it from the rest of the organism. Joachimiak and his colleagues from Argonne, the Scripps Research Institute and Rice University describe their discovery in a study published online June 21, 2018, in Cell Chemical Biology.
“We hope that these compounds will be able to be used in cancer treatment or killing other bacteria that do not have these sequester proteins.” — Andrzej Joachimiak, Argonne Distinguished Fellow
“The chemical is tightly bound to a protein and cannot then react with the DNA and damage it,” said Joachimiak, who directs Argonne’s Structural Biology Center and the multi-institutional Midwest Center for Structural Genomics. The work raises the prospect of engineering new sequester proteins that can bind to other chemicals for medical therapeutics.
“We hope that these compounds will be able to be used in cancer treatment or killing other bacteria that do not have these sequester proteins,” Joachimiak said.
The work also carries important implications for understanding how human cancer cells develop resistance to natural product-based chemotherapies.
“Thanks to this discovery, we now know something about a new mechanism of resistance that’s never been reported before for enediyne antitumor antibiotics,” said the study’s lead author, Ben Shen, professor of chemistry at the Scripps Research Florida campus. “This mechanism could be clinically relevant for patients getting these drugs, so it’s very important to study it further.”
The new mechanism involves three genes — tnmS1, tnmS2 and tnmS3 — that encode proteins that allow bacteria to resist the effects of a type of enediyne called tiancimycin, which holds promise for new cancer drugs. The proteins work by binding to tiancimycins and keeping them separate from the rest of the organism.
Natural products, such as enediynes, are one of the best sources of new drugs and drug leads, Shen noted. “They possess enormous structural and chemical diversity compared with molecules that are made in the lab,” he said.
Two enediyne products are already in wide use as cancer drugs. But patients who take them often develop resistance. Possibly playing a role in this resistance is the microbiome, the vast community of microbes that live within the human body.
After discovering the three genes and how they work, the investigators studied the prevalence of the genes in other microorganisms. They were surprised to find that the genes were also present in microorganisms commonly found in the human microbiome, which raises new questions.
“I can rationalize why the producing organism would have these genes, because it needs to protect itself from its own metabolites,” Shen said. “But why do other organisms need these resistance genes?” He noted that gut microbes might be able to pass the products of these genes on to their human hosts, which could contribute to drug resistance.
The findings suggest that the human microbiome might affect the efficacy of enediyne-based drugs and should be taken into account when developing new chemotherapies, Shen said. “Future efforts to survey the human microbiome for resistance elements should be an important part of natural product-based drug discovery programs.”
Argonne’s Advanced Protein Characterization Facility produced the proteins for the study. The molecular structure of the proteins were then determined using Argonne’s Structural Biology Center X-ray beamlines at sector 19 of the Advanced Photon Source, a DOE Office of Science User Facility.
“This particular compound has triple bonds, which are rare in biological systems,” Joachimiak said of enediyne. Most biological bonds link two atoms via single or double pairs of electrons, but this one bonds atoms via three pairs of electrons. Because triple bonds are more chemically reactive, they lead to the creation of new substances that the bacteria produce for self-defense, he said.
“Resistance to Enediyne Antitumor Antibiotics by Sequestration” was published in Cell Chemical Biology. Argonne co-authors included the Biosciences division’s Changsoo Chang and Gyorgy Babnigg, as well as Boguslaw Nocek, now of Abbvie.
This study was funded by the National Institutes of Health.
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