Fungal Biotransformation of Tetracycline Antibiotics

Tetracyclines were among the first of the modern era “magic bullet” antibiotics, exhibiting broad-spectrum activity against a wide array of infectious diseases, including anthrax, cholera, bubonic plague, syphilis, chlamydia, and tuberculosis, as well as Lyme and Legionnaire’s disease. In addition to their transformative role in human healthcare, tetracyclines played a major role in controlling disease and enhancing productivity in agriculture (e.g., livestock, aquaculture and crops). Unfortunately, widespread use of tetracyclines in human health and agriculture has resulted in the emergence of resistance, exacerbated by the annual release of thousands of ton into the environment via urban sewage, rural runoff, and industrial sludge. Once in the environment, tetracyclines can be distributed via surface and groundwater, accumulating in soil and plants, entering the food chain, and exposing pathogens, as well as animals and humans, to long- term sub therapeutic antibiotic dosing. Prolonged exposure presents a very real danger of selecting for and encouraging greater levels of antibiotic resistance.

Our study, published in The Journal of Organic Chemistry, reports for the first time that selected strains of fungi provide a hitherto unappreciated level of environmental protection, by degrading tetracyclines. While knowledge of a natural pathway for biodegradation comes as a relief, it also forewarns of a potential future risk should tetracycline degrading enzymes in fungi transfer to bacterial pathogens! In response to this threat we describe a rare and largely overlooked class of tetracycline-like fungal metabolites, that are immune to fungal degradation and exhibit superior antibiotic activity against vancomycin resistant Enterococci (>270-fold better than tetracyclines). This knowledge can inform the development of new tetracycline antibiotics, to secure their future in combatting infectious diseases.

Watch an explainer video by lead researcher Zhou Shang. (Note: navigate to the third slide to access the video.)


A molecular code for endosomal recycling of phosphorylated cargos by the SNX27–retromer complex

6 September 2016

The paper in Nature Structural & Molecular Biology is not of direct biomedical relevance, but describes the analysis of a protein complex involved in neurodegenerative diseases including Parkinson’s, Alzheimer’s and Down Syndrome. The work defines the molecular code that controls how hundreds of different 'cargo' proteins associate with the SNX27-retromer complex, using a combination of ultra-high resolution X-ray crystallography, bioinformatics, and cellular studies of protein-protein interactions. When these 'cargo' interactions are blocked are degraded more rapidly than normal leading to defects in cell homeostasis and cell-cell communication.


An endosomal tether undergoes an entropic collapse to bring vesicles together

30 August 2016

Each of the cells that make up the organs of our bodies is enclosed in a plasma membrane, a complex sheet made up of lipids and proteins. The plasma membrane plays a crucial role in detecting signals for growth or in taking nutrients up into the cell in a process termed endocytosis. The aim of this study, lead by Professor Marino Zerial and Professor Stephan Grill from the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, was to determine how a vesicle, which has pinched off from the plasma membrane during endocytosis, finds its destination in the cell, an organelle called endosome. This process uses a protein called Rab5, a small protein that can switch between active and inactive forms, and a long filamentous protein, called EEA1.

Parton and his team at IMB showed using high resolution electron microscopy that EEA1 proteins form a dense layer of filaments - a hairy coat - which extends out from the surface of endosomes. The latest study, published in Nature, which is the result of a long-standing collaboration between the Parton and Zerial groups, shows that vesicles covered in active Rab5 bind to the hairy EEA1 coat. This triggers the individual EEA1 filaments to change their conformation - instead of being extended they become flexible, generating an entropic collapse force. This force allows the vesicle to reach the surface of the endosome and fuse with its membrane. This may be a universal mechanism which makes sure that vesicles find the right destination within the cell and that they deliver their contents efficiently to their targets. But the entropic collapse may also be a general mechanism of many cellular proteins that can store energy in their conformation and release it upon a trigger.

[Right] Capture of a vesicle by an endosome by the tethering factor EEA1 binding Rab5. Active Rab5 (shiny blue particles) induces a change in flexibility of EEA1 (green filaments) generating an entropic collapse force that pulls the vesicle toward the target membrane to dock and fuse. For futher details see Murray et al, Nature 2016. Image by Mario Avellaneda.



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