Tag: Chemical Biology

Scientists Discover Unexpected Effects of Common Food Preservative

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Foods such as yogurts, canned vegetables, and packaged breads frequently include preservatives that leverage the antimicrobial properties of substances like lantibiotics, including those similar to nisin, to ensure their longevity and safety. These additives, while essential for preventing microbial growth that can lead to spoilage, are now being studied for their broader implications on health, particularly their interactions with the human gut microbiome. Recent findings by researchers at the University of Chicago point to the dual action of these compounds, capable of targeting both detrimental pathogens and crucial beneficial bacteria within the gut, thereby raising important questions about their long-term effects on digestive health and microbial diversity.

Research on a widely used food preservative known for its ability to eliminate pathogens indicates it also impacts helpful bacteria, posing a risk to the gut microbiome’s equilibrium.

To extend the shelf life of food items, manufacturers commonly incorporate preservatives into their products. These substances are intended to eliminate microorganisms that may cause the food to deteriorate. While traditional preservatives such as sugar, salt, vinegar, and alcohol have a long history of use, contemporary food products often list more obscure additives like sodium benzoate, calcium propionate, and potassium sorbate on their labels.

Bacteria produce chemicals called bacteriocins to kill microbial competitors. These chemicals can serve as natural preservatives by killing potentially dangerous pathogens in food. Lanthipeptides, a class of bacteriocins with especially potent antimicrobial properties, are widely used by the food industry and have become known as “lantibiotics” (a scientific portmanteau of lanthipeptide and antibiotics).

Despite their widespread use, however, little is known about how these lantibiotics affect the gut microbiomes of people who consume them in food. Microbes in the gut live in a delicate balance, and commensal bacteria provide important benefits to the body by breaking down nutrients, producing metabolites, and—importantly—protecting against pathogens. If too many commensals are indiscriminately killed off by antimicrobial food preservatives, opportunistic pathogenic bacteria might take their place and wreak havoc—a result no better than eating contaminated food in the first place.

Effects on good and bad bacteria

A new study published in ACS Chemical Biology by scientists from the University of Chicago found that one of the most common classes of lantibiotics has potent effects both against pathogens and against the commensal gut bacteria that keep us healthy.

Nisin is a popular lantibiotic used in everything from beer and sausage to cheese and dipping sauces. It is produced by bacteria that live in the mammary glands of cows, but microbes in the human gut produce similar lantibiotics too. Zhenrun “Jerry” Zhang, Ph.D., a postdoctoral scholar in the lab of Eric Pamer, MD, the Donald F. Steiner Professor of Medicine and Director of the Duchossois Family Institute at UChicago, wanted to study the impact of such naturally-produced lantibiotics on commensal gut bacteria.

“Nisin is, in essence, an antibiotic that has been added to our food for a long time, but how it might impact our gut microbes is not well studied,” Zhang said. “Even though it might be very effective in preventing food contamination, it might also have a greater impact on our human gut microbes.”

He and his colleagues mined a public database of human gut bacteria genomes and identified genes for producing six different gut-derived lantibiotics that closely resemble nisin, four of which were new. Then, in collaboration with Wilfred A. van der Donk, Ph.D., the Richard E. Heckert Endowed Chair in Chemistry at the University of Illinois Urbana-Champaign, they produced versions of these lantibiotics to test their effects on both pathogens and commensal gut bacteria. The researchers found that while the different lantibiotics had varying effects, they killed pathogens and commensal bacteria alike.

“This study is one of the first to show that gut commensals are susceptible to lantibiotics, and are sometimes more sensitive than pathogens,” Zhang said. “With the levels of lantibiotics currently present in food, it’s very probable that they might impact our gut health as well.”

Harnessing the power of lantibiotics

Zhang and his team also studied the structure of peptides in the lantibiotics to better understand their activity, in the interest of learning how to use their antimicrobial properties for good. For example, in another study, the Pamer lab showed that a consortium of four microbes, including one that produces lantibiotics, help protect mice against antibiotic-resistant Enterococcus infections. They are also studying the prevalence of lantibiotic-resistant genes across different populations of people to better understand how such bacteria can colonize the gut under different conditions and diets.

“It seems that lantibiotics and lantibiotic-producing bacteria are not always good for health, so we are looking for ways to counter the potential bad influence while taking advantage of their more beneficial antimicrobial properties,” Zhang said.

Reference: “Activity of Gut-Derived Nisin-like Lantibiotics against Human Gut Pathogens and Commensals” by Zhenrun J. Zhang, Chunyu Wu, Ryan Moreira, Darian Dorantes, Téa Pappas, Anitha Sundararajan, Huaiying Lin, Eric G. Pamer and Wilfred A. van der Donk, 31 January 2024, ACS Chemical Biology.
DOI: 10.1021/acschembio.3c00577

The study was supported by the GI Research Foundation, the Howard Hughes Medical Institute, the National Institutes of Health (grants R01AI095706, P01 CA023766, U01 AI124275, and R01 AI042135) and the Duchossois Family Institute at UChicago. Additional authors include Chunyu Wu, Ryan Moreira, and Darian Dorantes from the Univeristy of Illinois Urbana-Champaign, and Téa Pappas, Anitha Sundararajan, and Huaiying Lin from UChicago.

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February 6, 2024
Synthesizing and identifying potential biomarkers to explore uncharted biochemistry

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Nature, Published online: 05 February 2024; doi:10.1038/d41586-023-04105-z

Public repositories of metabolomics data are expanding rapidly and can be leveraged to uncover previously undescribed metabolites. Reverse metabolomics is a workflow in which thousands of small compounds are synthesized using combinatorial chemistry, and their molecular ‘fingerprints’ are then used to discover where they are localized in tissues and biological fluids and how they are associated with health and disease in humans.

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February 5, 2024
The Surprising Phenomenon of Kinetic Asymmetry

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A team of researchers has uncovered a novel way that molecules can interact non-reciprocally without external forces, through a mechanism involving kinetic asymmetry. This discovery challenges traditional views on molecular interactions and could have profound implications for understanding life’s evolution and designing molecular machines. Credit: SciTechDaily.com

Scientists have found that molecules can interact in a non-reciprocal manner without external forces, a discovery that could change our understanding of molecular interactions and the evolution of life.

Researchers from the University of Maine and Penn State discovered that molecules experience non-reciprocal interactions without external forces.

Fundamental forces such as gravity and electromagnetism are reciprocal, where two objects are attracted to each other or are repelled by each other. In our everyday experience, however, interactions don’t seem to follow this reciprocal law. For example, a predator is attracted to prey, but the prey tends to flee from the predator. Such non-reciprocal interactions are essential for complex behavior associated with living organisms.

For microscopic systems such as bacteria, the mechanism of non-reciprocal interactions has been explained by hydrodynamic or other external forces, and it was previously thought that similar types of forces could explain interactions between single molecules.

In work published in the prestigious Cell Press journal Chem, UMaine theoretical physicist R. Dean Astumian and collaborators Ayusman Sen and Niladri Sekhar Mandal at Penn State have published a different mechanism by which single molecules can interact non-reciprocally without hydrodynamic effects.

This mechanism invokes the local gradients of reactants and products due to the reactions facilitated by every chemical catalyst, a biological example of which is an enzyme. Because the response of a catalyst to the gradient depends on the catalyst’s properties, it is possible to have a situation in which one molecule is repelled by, but attracts, another molecule.

Kinetic Asymmetry: A Key Factor

The authors’ “Eureka moment” occurred when, in their discussion, they realized that a property of every catalyst known as the kinetic asymmetry controls the direction of response to a concentration gradient. Because kinetic asymmetry is a property of the enzyme itself, it can undergo evolution and adaptation. The non-reciprocal interactions allowed by kinetic asymmetry also play a crucial role in allowing molecules to interact with each other, and may have played a critical role in the processes by which simple matter becomes complex.

A graphic illustrating the four possible interactions between two particles, where the arrows indicate the force experienced by the particle of that color due to the gradient surrounding the particle of the other color. The interactions shown in the upper left-hand and lower right-hand corners illustrate reciprocal interactions where the two particles attract each other, or where they repel each other, respectively. The upper right-hand graphic illustrates a situation where the red particle attracts the blue particle, but the blue particle repels the red particle. The lower left-hand graphic illustrates a situation where the red particle repels, but is attracted to, the blue particle. Graphic courtesy of R. Dean Astumian. Credit: R. Dean Astumian

Much previous work has been done by other researchers on what happens when non-reciprocal interactions occur. These efforts have played a central role in the development of a field known as “active matter.” In this earlier work, the non-reciprocal interactions were introduced by incorporation of ad hoc forces.

The research described by Mandal, Sen, and Astumian, however, describes a basic molecular mechanism by which such interactions can arise between single molecules. This research builds on earlier work in which the same authors showed how a single catalyst molecule could use energy from the reaction it catalyzed to undergo directional motion in a concentration gradient.

Impact on Biomolecular Machines and Early Life

The kinetic asymmetry that features in determining the non-reciprocal interactions between different catalysts has also been shown to be important for the directionality of biomolecular machines, and has been incorporated in the design of synthetic molecular motors and pumps.

The collaboration between Astumian, Sen, and Mandal aims to reveal the organizational principles behind loose associations of different catalysts that may have formed the earliest metabolic structures that eventually led to the evolution of life.

“We’re at the very beginning stages of this work, but I see understanding kinetic asymmetry as a possible opportunity for understanding how life evolved from simple molecules,” Astumian says. “Not only can it provide insight into complexification of matter, kinetic asymmetry can also be used in the design of molecular machines and associated technologies.”

Reference: “A molecular origin of non-reciprocal interactions between interacting active catalysts” by Niladri Sekhar Mandal, Ayusman Sen and R. Dean Astumian, 29 December 2023, Chem.
DOI: 10.1016/j.chempr.2023.11.017

Astumian joined UMaine’s Department of Physics and Astronomy in 2001. His research focuses on biophysics, condensed matter physics, and chemically driven molecular machines.

He was named a fellow of the American Association for the Advancement of Science (AAAS) In 2016. His other honors include the Galvani Prize of the Bio-electrochemical Society, the Humboldt Prize, the Feynman Prize, and the Royal Society of Chemistry Horizon Prize, the Perkin Prize in physical organic chemistry.

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December 31, 2023
Breakthrough Discovery Opens Up New Possibilities for Ion Channel-Targeting Drugs

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A groundbreaking discovery of side openings in BK ion channels by researchers offers a new pathway for developing selective drugs to target these channels, addressing a significant challenge in ion channel drug development. Credit: SciTechDaily.com

Ion channels are crucial in health and disease, making them significant targets for drug development. However, selectively targeting specific ion channels remains a major challenge. Researchers at Weill Cornell Medicine and RMIT University in Australia have discovered unique side openings in BK channels, a type of ion channel. These openings may allow drug molecules to access the channels selectively. This discovery, detailed in a recent paper published in Nature Chemical Biology, could lead to new drugs targeting the BK channel for treating various diseases.

Understanding Ion Channels and BK Channels

Ion channels are tunnel-like structures embedded in cell membranes that control the flow of charged molecules in or out of cells, which is required for many biological processes. BK channels, for instance, conduct the flow of potassium ions and inherited mutations in these channels have been linked to problems in multiple organ systems.

“The discovery of a site where small molecules can selectively access this important type of ion channel is an exciting development,” said study co-senior author Dr. Crina Nimigean, professor of physiology and biophysics in anesthesiology at Weill Cornell Medicine.

The other co-senior author of the study is Dr. Toby Allen, a professor at RMIT University in Melbourne, Australia. The first author, Dr. Chen Fan, was a postdoctoral research associate in the Nimigean Lab in the Department of Anesthesiology during the study.

Exploring BK Channel Structures

Dr. Nimigean and her team have been exploring the structure and function of BK channels, both directly and with experiments on a bacterial version called MthK that is easier to study in the laboratory. Recently, they observed that a family of MthK- and BK-blocking compounds—not suitable as drugs but useful as laboratory tools—can access and effectively plug the MthK channel, or “pore,” even when structural imaging shows that the entrance to the pore is fully closed.

“Since these compounds wouldn’t have direct access to the pore in this closed state, we wondered how they were able to get in,” Dr. Nimigean said.

To resolve this conundrum, the researchers turned to structural imaging methods, experiments with normal and mutated MthK, and, in Dr. Allen’s laboratory, computer modeling of the interactions between the channel-blocking compounds and the MthK ion channel.

They discovered that when MthK is in the closed state, the structure develops large openings on its sides through which the MthK-blocking compounds can access the ion-conducting pore. These openings are inside the cell membrane, so the MthK-blocking compounds must first travel a short distance into the membrane to reach them.

The researchers also observed from existing structural data that side-openings or “fenestrations” like those in the MthK channels are present in BK channels as well.

Potential for Selective Drug Development

Scientists believe that BK-blocking or -activating drugs could help treat disorders such as epilepsy and hypertension. However, no selective BK channel-modulating drug exists, in part because little is known about how changes in the BK channel structure relate to the channel’s function. Another problem is drugs that affect BK channels also interact with other ion channels because they typically target the entrance to the potassium-conducting chute or “pore,” which is not very different from the pores of other types of ion channels. Such indiscriminate interactions could lead to havoc in the body.

“These fenestrations are unique to BK-type channels, which suggests that future drugs targeting these sites could work as selective BK channel blockers or activators,” Dr. Nimigean said.

She and her team are planning follow-up experiments in BK channels and hope to use their findings to discover selective BK channel-modulating compounds that could be developed into drugs.

Reference: “Calcium-gated potassium channel blockade via membrane-facing fenestrations” by Chen Fan, Emelie Flood, Nattakan Sukomon, Shubhangi Agarwal, Toby W. Allen and Crina M. Nimigean, 31 August 2023, Nature Chemical Biology.
DOI: 10.1038/s41589-023-01406-2

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December 6, 2023