(Photo: University of Leeds)

A previously unknown mechanism that allows cells to bind and isolate toxic substances away from the rest of the cellular contents has been discovered by scientists from the Scripps Research Florida campus. The research, which was published yesterday in Cell Chemical Biology, could have significant implications for how tumours develop resistance to certain types of chemotherapy.

Roughly 50% of all the drugs we currently have available are either natural substances, or compounds that have been derived from naturally occurring chemicals. This includes every day painkillers, such as aspirin (derived from salicin in willow tree bark), opioids, such as morphine (obtained from opium within the Papaver somniferum poppy), and even some anti-cancer medications, including SMANCS (derived from neocarzinostatin in Streptomyces carzinostaticus). Many drug developers still rely heavily on studying naturally occurring compounds to identify potential new medications.

“They possess enormous structural and chemical diversity compared with molecules that are made in the lab,” said Ben Shen, PhD, senior author of the paper and Professor and Co-Chair of the Scripps Research Department of Chemistry.

One question that has remained unanswered, however, is how the organisms that create such toxic, anti-cancer compounds are able to survive the harmful effects they entail. Now, Dr Shen and his team have uncovered a mechanism whereby cells use proteins to bind the toxic compounds and sequester them away from the rest of the cells’ contents. Not only does this teach us more about the organisms that can produce anti-cancer agents, it also offers insight into how human cancer cells may be able to develop resistance to therapies based on those drugs.

“Thanks to this discovery, we now know something about the mechanisms of resistance that’s never been known before for the enediyne antitumor antibiotics,” said Dr Shen.

The chemical structure of an enediyne.

The study focused on enediynes, a class of natural products produced by soil-dwelling actinomycetes bacteria. Two enediyne-based compounds have received FDA approval for cancer treatment in the past, but the treatment is hindered by the development of drug-resistance over time that ultimately leads to the patient becoming immune to the therapy. Previous research has identified two mechanisms by which bacteria can protect themselves from these compounds, although it is unclear if a similar process is used by cancer cells in humans.

This new research outlines a third, previously unknown mechanism within bacteria that may be implicated in drug resistance. The team identified three genes, tnmS1, tnmS2, and tnmS3, which encode proteins that enable the bacterial cells to resist a type of enediynes known as tiancimycins. Through the activity of these genes, the cells can bind and isolate the compounds in a way that prevents them from causing harm.

The team then investigated the prevalence of these genes in organisms other than actinomycetes. Surprisingly, they found that they occurred in a range of other microorganisms, including a several organisms known to be common in the human microbiome.

“This raises a lot of questions that no one has ever asked before,” said Dr Shen. “I can rationalize why the producing organism would have these genes, because it needs to protect itself from its own metabolites. But why do other microorganisms need these resistance genes?

“These findings raise the possibility that the human microbiota might impact the efficacy of enediyne-based drugs and should be taken into consideration when developing new chemotherapies. Future efforts to survey the human microbiome for resistance elements should be an important part of natural product-based drug discovery programs.”