Scientists discover novel compounds in Arctic marine bacteria that could combat antibiotic-resistant infections and pave the way for next-generation treatments.
Study: Bioprospecting of inhibitors of EPEC virulence from metabolites of marine actinobacteria from the Arctic Sea. Image Credit: Risto Raunio / Shutterstock
Antibiotics are the linchpin of modern medicine: without them, anyone with open wounds or needing surgery would be at constant risk of dangerous infections. Yet, we continue to face a global antibiotic crisis as more and more resistant strains of bacteria evolve. In contrast, the discovery rate of fundamentally new antibiotics has been much slower.
New Hope from Unexplored Environments
But there is reason for hope: 70% of all currently licensed antibiotics have been derived from actinobacteria in the soil, and most environments on Earth have not yet been prospected for them. Thus, focusing the search on actinobacteria in other habitats is a promising strategy—especially from unexplored environments like the Arctic Sea—especially if this were to yield novel molecules that neither kill bacteria outright nor stop them from growing but only reduce their ‘virulence’ or capacity for causing disease. This is because it is hard for targeted pathogenic strains to evolve resistance under these conditions, while such antivirulence compounds are also less likely to cause unwanted side effects.
Advanced Screening Assays Reveal New Compounds
“In our study, we utilized high-content screening assays (FAS-HCS) and Tir translocation assays to specifically identify antivirulence and antibacterial compounds from actinobacteria extracts,” said Dr Päivi Tammela, a professor at the University of Helsinki, Finland, and the corresponding author of a new study in Frontiers in Microbiology. “We discovered two distinct compounds: a large phospholipid that inhibits enteropathogenic E. coli (EPEC) virulence without affecting its growth, and a growth-inhibiting compound, both in actinobacteria from the Arctic Ocean.”
High-throughput automated screening of these candidate compounds was performed using an advanced workflow designed to handle the complex nature of microbial extracts. Tammela and colleagues developed a new suite of methods that simultaneously test for the antivirulence and antibacterial effects of hundreds of unknown compounds. They targeted an EPEC strain that causes severe—and sometimes deadly—diarrhea in children under five, especially in developing countries. EPEC causes disease by adhering to cells in the human gut. Once it adheres to these cells, EPEC injects so-called ‘virulence factors’ into the host cell to hijack its molecular machinery, ultimately killing it.
Discovery of Antivirulence and Antibacterial Compounds
The tested compounds were derived from four species of actinobacteria, isolated from invertebrates sampled in the Arctic Sea off Svalbard during an expedition of the Norwegian research vessel ‘Kronprins Haakon’ in August 2020. These bacteria were then cultured, their cells extracted, and their contents separated into fractions. Each fraction was then tested in vitro against EPEC adhering to cultured colorectal cancer cells.
The researchers found two previously unknown compounds with distinct biological activities: one from an unknown strain (T091-5) in the genus Rhodococcus and another from an unknown strain (T160-2) of Kocuria. The compound from T091-5, identified as a large phospholipid, showed powerful antivirulence effects by inhibiting the formation of actin pedestals and the binding of EPEC to the Tir receptor on the host cell’s surface. The compound from T160-2 exhibited strong antibacterial properties by inhibiting the growth of EPEC bacteria.
Promising Results and Next Steps
Detailed analysis revealed that the phospholipid from T091-5 does not inhibit bacterial growth, making it a promising candidate for antivirulence therapy, as it reduces the likelihood of resistance development. In contrast, the compound from T160-2 was found to inhibit growth and is being investigated further for its potential as a novel antibiotic.
The researchers used HPLC-HR-MS2 to isolate and identify these compounds, with the phospholipid’s molecular weight around 700 and its specific role in disrupting the interaction between EPEC and host cells. “The next steps are the optimization of the culture conditions for compound production and the isolation of sufficient amounts of each compound to elucidate their respective structures and further investigate their respective bioactivities,” said Tammela.
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