Cystic fibrosis-associated bacteria could help fight back against antibiotic resistance

ScienceDaily (May 28, 2011) — A bacteria which infects people with cystic fibrosis could help combat other antibiotic-resistant microbes, according to a team from Cardiff and Warwick Universities. Continuous use of existing antibiotics means that resistant bacteria are now causing major health problems all over the world. New antibiotics are urgently needed to combat the emergence of multidrug-resistant bacteria such as the MRSA superbug.

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Now a surprising source of hope has emerged in the form of Burkholderia, a group of bacteria which can cause severe lung infections in people with the genetic disorder cystic fibrosis. However, the Cardiff and Warwick team has now discovered antibiotics from Burkholderia are effective against MRSA and even other cystic fibrosis infecting bacteria.

Dr Eshwar Mahenthiralingam, of Cardiff University's School of Biosciences, Cardiff University, has been studying Burkholderia for the last decade. Using forensic fingerprinting tests to genetically identify the bacteria, Dr Mahenthiralingam's research group has tracked strains all over the world and helped develop guidelines to prevent it spreading.

By the summer of 2007, Dr Mahenthiralingam had built up a large collection of Burkholderia bacteria. He and his team then decided to screen them for antibiotics active against other bacteria, particularly drugs with the potential to kill other bacteria that infect cystic fibrosis patients. Over the next two years, Dr Mahenthiralingam's team discovered that around one quarter of Burkholderia bacteria have very strong antibiotic activity on multidrug-resistant pathogens such as MRSA. One particular strain, Burkholderia ambifaria, was found to produce two very potent antibiotics active on resistant bacteria, in particular Acinetobacter baumanii.

The chemical structures of the antibiotics, called enacyloxins, were determined by Professor Gregory Challis and Dr. Lijiang Song at the University of Warwick, demonstrating that they belong to one of the most successful families of natural product drugs, the polyketides. Other examples of polyketides include erythromycin, which is used to cure many bacterial infections, and doxorubin, used as an anti-cancer drug. Professor Challis commented: "The combination of enzymes used by Burkholderia to make the enacyloxins is very unusual. Our insights into this process should allow us to use cutting edge synthetic biology techniques to produce novel enacyloxin analogues with improved pharmaceutical properties."

The team's findings have now been published in the journal Chemistry and Biology. Dr Mahenthiralingam commented: "Burkholderia are soil bacteria like Streptomyces, which are the source of most of our current antibiotics. Our research therefore offers real hope of a completely new source for the identification and engineering of highly potent antibiotics. With antibiotic resistant bacteria causing great suffering around the world, these new sources are urgently needed."

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Novel pathway regulating angiogenesis: May fight retinal disease, cancers

ScienceDaily (May 31, 2011) — Scientists have identified in the journal Nature a new molecular pathway used to suppress blood vessel branching in the developing retina -- a finding with potential therapeutic value for fighting diseases of the retina and a variety of cancers.

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Researchers report that myeloid cells, blood cells involved in the immune system, use this molecular pathway to guide blood vessel patterning in the retina. Furthermore, in the same study researchers were able to reverse this pathway to accelerate the growth of branching vessels, which could be important to developing new methods for repairing damaged tissues.

"We show in the setting of retina that myeloid cells use this pathway to direct vascular traffic," explained Richard Lang Ph.D., senior investigator on the study and director of the Visual Systems Group in the Division of Ophthalmology at Cincinnati Children's Hospital Medical Center. "We think modulation of this pathway might become a promising therapeutic option.''

The study, to be published online May 29, demonstrates how retinal myeloid cells regulate blood vessel branching in the still-developing retinas of postnatal mice by using the Wnt protein signaling network. The Wnt pathway is known for its role in embryonic and early development as well as in cancer. Although myeloid cells play an important part in the immune system, these cells are also found in many different tumor types and promote tumor progression.

Through a series of experiments in cell cultures and mouse models, researchers determined the new pathway works by myeloid cells utilizing the Wnt pathway to regulate expression of a gene known as Flt1. Flt1 encodes a protein called vascular endothelial growth factor receptor-1 (VEGFR1), which suppresses vascular growth by binding vascular endothelial growth factor (VEGF). The expression of Flt1 can be adjusted so that when ramped up it inhibits VEGF and vascular branching, or when turned down it allows VEGF to increase branching.

Dr. Lang said the Wnt-Flt1 response is a new pathway for regulating VEGF-stimulated angiogenesis (blood vessel formation). This presents a number of new research opportunities to test its influence on retinal diseases that are often associated with abnormal blood vessel development and in tumor formation, he added.

The current study's first author, James (Tony) Stefater, a member of Dr. Lang's laboratory, is an M.D.-Ph.D. graduate student at the University of Cincinnati College of Medicine. Lang, Stefater and their colleagues are already conducting new experiments to see how the pathway influences molecular reactions in retinal disease and in cancer. The cancer studies are being done in collaboration with Jeff Pollard, Ph.D., a cancer cell biologist at the Albert Einstein College of Medicine and co-author on the current study.

The study was supported by funding from the National Eye Institute of the National Institutes of Health, the Howard Hughes Medicine Institute, and included collaborators from those institutions as well as the London Research Institute (Vascular Biology Laboratory) in the United Kingdom and the Center for Skeletal Disease Research, Grand Rapids, Mich.

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