Interference With Quorum-Sensing Signal Biosynthesis as a Promising Therapeutic Strategy Against Multidrug-Resistant Pathogens.
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ABSTRACT:
SUBMITTER: Fleitas Martinez O
PROVIDER: S-EPMC6371041 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
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Project description:Members of the diazeniumdiolate class of natural compounds show potential for drug development because of their antifungal, antibacterial, antiviral, and antitumor activities. Yet, their biosynthesis has remained elusive to date. Here, we identify a gene cluster directing the biosynthesis of the diazeniumdiolate compound fragin in Burkholderia cenocepacia H111. We provide evidence that fragin is a metallophore and that metal chelation is the molecular basis of its antifungal activity. A subset of the fragin biosynthetic genes is involved in the synthesis of a previously undescribed cell-to-cell signal molecule, valdiazen. RNA-Seq analyses reveal that valdiazen controls fragin biosynthesis and affects the expression of more than 100 genes. Homologs of the valdiazen biosynthesis genes are found in various bacteria, suggesting that valdiazen-like compounds may constitute a new class of signal molecules. We use structural information, in silico prediction of enzymatic functions and biochemical data to propose a biosynthesis route for fragin and valdiazen.
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Project description:Members of the diazeniumdiolate class of natural compounds show great potential for drug development. Yet, their biosynthesis has remained elusive to date. Here, we identify a gene cluster directing the biosynthesis of the diazeniumdiolate compound fragin in Burkholderia cenocepacia H111. We provide evidence that fragin is a metallophore and that metal chelation is the molecular basis of its antifungal activity. We also show that a subset of the fragin biosynthetic genes is involved in the synthesis of a novel cell-to-cell signaling molecule, valdiazen. RNA-Seq analyses revealed that valdiazen not only controls fragin biosynthesis but affects expression of more than 100 genes. Homologs of the valdiazen biosynthesis genes are found in various bacteria, suggesting that valdiazen is the first representative of a new signal molecule class. Using structural information, in silico prediction of enzymatic functions and biochemical data we propose a biosynthesis route for fragin and valdiazen.
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Project description:Catheter-associated urinary tract infections (CAUTI) is an alarming hospital based disease with the increase of multidrug resistance (MDR) strains of Proteus mirabilis. Cases of long term hospitalized patients with multiple episodes of antibiotic treatments along with urinary tract obstruction and/or undergoing catheterization have been reported to be associated with CAUTI. The cases are complicated due to the opportunist approach of the pathogen having robust swimming and swarming capability. The latter giving rise to biofilms and probably inducible through autoinducers make the scenario quite complex. High prevalence of long-term hospital based CAUTI for patients along with moderate percentage of morbidity, cropping from ignorance about drug usage and failure to cure due to MDR, necessitates an immediate intervention strategy effective enough to combat the deadly disease. Several reports and reviews focus on revealing the important genes and proteins, essential to tackle CAUTI caused by P. mirabilis. Despite longitudinal countrywide studies and methodical strategies to circumvent the issues, effective means of unearthing the most indispensable proteins to target for therapeutic uses have been meager. Here, we report a strategic approach for identifying the most indispensable proteins from the genome of P. mirabilis strain HI4320, besides comparing the interactomes comprising the autoinducer-2 (AI-2) biosynthetic pathway along with other proteins involved in biofilm formation and responsible for virulence. Essentially, we have adopted a theoretical network model based approach to construct a set of small protein interaction networks (SPINs) along with the whole genome (GPIN) to computationally identify the crucial proteins involved in the phenomenon of quorum sensing (QS) and biofilm formation and thus, could be therapeutically targeted to fight out the MDR threats to antibiotics of P. mirabilis. Our approach utilizes the functional modularity coupled with k-core analysis and centrality scores of eigenvector as a measure to address the pressing issues.
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Project description:Quorum sensing is a promising target for next-generation anti-infectives designed to address evolving bacterial drug resistance. The autoinducer-2 (AI-2) is a key quorum-sensing signal molecule which regulates bacterial group behaviors and is recognized by many Gram-negative and Gram-positive bacteria. Here we report a synthetic mammalian cell-based microbial-control device that detects microbial chemotactic formyl peptides through a formyl peptide sensor (FPS) and responds by releasing AI-2. The microbial-control device was designed by rewiring an artificial receptor-based signaling cascade to a modular biosynthetic AI-2 production platform. Mammalian cells equipped with the microbial-control gene circuit detect formyl peptides secreted from various microbes with high sensitivity and respond with robust AI-2 production, resulting in control of quorum sensing-related behavior of pathogenic Vibrio harveyi and attenuation of biofilm formation by the human pathogen Candida albicans. The ability to manipulate mixed microbial populations through fine-tuning of AI-2 levels may provide opportunities for future anti-infective strategies.
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