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Identification of strong constitutive promoters in Burkholderia to activate natural product production in Gram-negative bacteria

ABSTRACT: Gram-negative bacteria are an emerging source of natural products with pharmaceutical potential. However, the limited availability of essential genetic tools for drug discovery and sustainable production remains a challenge. Burkholderia serves as a promising source for such tools, as it produces diverse natural products and can be experimentally manipulated in the laboratory. Hence, this study aimed to identify strong and constitutive promoters from Burkholderia stagnalis TBRC 18363 for unlocking the potential of cryptic biosynthetic genes and enhance natural product production. Highly expressed genes were identified through transcriptomic analysis. Twenty-six promoters were evaluated in Escherichia coli and Pseudomonas putida reporter systems. Among all, promoters p2035 and p5642 exhibited superior performance in both systems. These promoters were selected for further investigation and were found to enhance the production titer of icosalide in B. stagnalis TBRC 18363 and FR900359, a Gq/11 protein inhibitor depsipeptide, in Chromobacterium vaccinii. This research emphasizes efficient promoters for target gene overexpression in Gram-negative bacteria.

ORGANISM(S): Burkholderia stagnalis

PROVIDER: GSE269653 | GEO | 2025/10/31

REPOSITORIES: GEO

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Project description:Pathogens that grow during infections must cope with the reactive oxygen species (ROS) released by host immune cells. Among the different strategies to prevent oxidative damage during infections, pathogenic bacteria have evolved mechanisms to reduce respiration and other cellular processes that are particularly sensitive to free radicals, obtaining energy preferentially by undergoing to fermentative metabolism. As fermentation produces fewer ATP per glucose than respiration, bacteria ensure an appropriate supply of energy by increasing the glycolytic flux. The opportunistic human pathogen Staphylococcus aureus is one such microbe but the underlying mechanism that enables S. aureus to induce fermentation during infections is still unclear. Here we show that the ComK-like regulator of natural competence that is present in many gram-positive bacteria is crucial to redirect S. aureus metabolism to fermentation during infection. ComK is cryptic in laboratory conditions but highly induced during infections or in response to infection-related cues, such as ROS. ComK induces the glycolytic flux and glucose consumption rate, a key step to redirect ATP production to fermentation. This licenses fermenting S. aureus to reduce oxidative damage while increasing DNA uptake by natural transformation. As a consequence, a comK-defective mutant shows an accumulation of ROS as well as DNA mutations that lower bacterial survival. This mutant shows no distinctive phenotype in laboratory conditions but is unable to cause infection in vertebrates or invertebrate infection models. ComK-mediated synchronization of natural transformation to fermentative metabolism may allow S. aureus, and probably other gram-positive bacteria, to use the fermentation acid end products to eliminate bacterial competitors while assimilating their DNA. Assimilated DNA may serve as a source of nucleotides for DNA repair or to promote genetic variability, thereby enabling a successful host colonization of this bacterium.

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Identification of strong constitutive promoters in Burkholderia to activate natural product production in Gram-negative bacteria

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