Streptomyces bacteria, which produce many of the antibiotics we rely on, carry a set of ancient molecular switches that may control when those drugs are made—and researchers have just found a way to flip those switches on command. These switches, called NLRs, are well known in plants and animals, where they trigger immune responses. But their role in bacteria has been almost entirely overlooked. The BacNLR project will systematically map what these proteins do in multicellular *Streptomyces*, which encode far more NLRs than typical bacteria. Early evidence links several of them to antibiotic production, development, and programmed cell death—suggesting they orchestrate key bacterial behaviours. The team has developed a method to artificially activate NLR signalling without needing to find each natural trigger. This allows them to study how NLRs regulate antibiotic output and to uncover entirely new cellular functions. Using bioinformatics and molecular experiments, they will define the full diversity of bacterial NLRs and the mechanisms behind them. This is fundamental science. It will not produce a new drug next year. But understanding how bacteria control antibiotic production could eventually offer a fresh strategy for tackling drug-resistant infections, and it will reshape our picture of how NLR signalling evolved across all domains of life.
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BacNLR is an ambitious high-risk/high-gain program to reveal the functional diversity of nucleotide-binding oligomerisation domain like receptors (NLRs) in multicellular bacteria that goes beyond their well-established role in eukaryotic immunity. NLRs are found in all domains of life, yet little is known about their role in bacteria because their existence has only recently been fully recognised. Unlike most bacteria, species of antibiotic-producing multicellular Streptomyces encode multiple NLRs with distinct signalling domains, suggesting that these proteins have diverse functions. We found that in Streptomyces several NLR-like proteins are linked to antibiotic production, development or share homology to eukaryotic NLRs shown to induce programmed cell death. We therefore hypothesise that NLR-signalling plays a crucial and so far unexplored role in several important cellular processes, including antibiotic production, immunity and multicellular behaviour. To reveal these novel cellular roles, I developed a method to synthetically activate NLR signalling in Streptomyces, overcoming the need to identify a specific stimulus for NLR activation. This breakthrough enables us now to study the impact of NLRs on regulating antibiotic production and to discover new and possibly unexpected cellular roles. In BacNLR, we will use bioinformatics to identify the full spectrum of NLR diversity in bacteria; determine the diverse functions of NLRs in multicellular Streptomyces and define the molecular mechanisms that underpin these functions. BacNLR will not only uncover new roles of NLR signalling but also reveal undamental new principles in the regulation of antibiotic production, providing an innovative strategy to combat the rise in drug-resistant pathogens. The gained knowledge will expand our current models about the evolution, and functional diversity of NLRs across all kingdoms and serve as a framework for engineering NLR signalling pathways in bacteria.
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