Tuesday, May 26, 2009

Potential Source of New Antibiotics Revealed

Potential Source of New Antibiotics Revealed

Addition of signaling molecules to S. coelicolor induced antibiotic production

Using genome mining, researchers have discovered a family of five new signaling molecules that induce methylenomycin antibiotic production in Streptomyces coelicolor bacteria. This finding could ultimately lead to the discovery of many new antibiotics.

The molecules, called 2-alkyl-4-hydroxymethylfuran-3-carboxylic acids (AHFCAs), offer great promise, the researchers say. "AHFCAs could act as chemical keys that could unlock hundreds of new antibiotics," says Christophe Corre, PhD, a research fellow in the department of chemistry at the University of Warwick, England. "Many of the antibiotic-like gene clusters encoded within streptomycete genomes are not expressed in the laboratory environment. Supplementing streptomycete cultures with various AHFCAs is expected to stimulate the production of novel bioactive molecules."

These molecules have the potential to turn on novel antibiotic production pathways in up to 50% of Streptomyces bacteria, Dr. Corre says.

Timely Research

"This study is particularly timely given the alarming and increasing incidence of multiply drug-resistant bacteria, which means that new antibiotics are urgently needed to replenish our dwindling arsenal of effective antibiotic drugs," he adds.

"[This research] adds another arrow to our quiver and gives us a little bit more potential for discovery of new classes of compounds that may overcome resistance," says Jo Handelsman, PhD, Howard Hughes Medical Institute professor and chair of the department of bacteriology and professor in the department of plant pathology at the University of Wisconsin, Madison.

A bacterial colony produces antibiotics to defend itself against attacks from other bacteria. Under threat, the colony produces a signal that starts antibiotic production. Because the amount of signaling molecule produced is tiny—measuring in the micrograms—analysis has been a challenge. Dr. Corre and colleagues at the John Innes Centre, Norwich, England, used the University of Warwick’s 700 MHz nuclear magnetic resonance machine to study the new molecules.

The researchers learned a great deal from the new full genetic S. coelicolor sequence. When they added this information to their knowledge of the signaling molecule, they were sure that AHFCAs could stimulate antibiotic production. Adding AHFCAs to S. coelicolor W81 proved that theory by stimulating the production of methylenomycin antibiotics. The methylenomycins are well-known antibiotics; however, analysis revealed that other streptomycetes might produce AHFCAs as well, Dr. Corre says.

New Antibiotic Class

These newly identified AHFCAs could form a new general class of antibiotic biosynthesis inducers with functions similar to the better-known gamma-butyrolactone (GBL) molecules. "It is worth it to mention that AHFCAs are chemically more stable than the previously known GBLs and are active at sub-micromolar concentrations," Dr. Corre says.

This study is particularly timely given the alarming and increasing incidence of multiply drug-resistant bacteria, which means that new antibiotics are urgently needed to replenish our dwindling arsenal of effective antibiotic drugs.
—Christophe Corre, PhD, University of Warwick

He adds that he and his colleagues are now seeking funding for a study that will examine precisely how AHFCAs induce antibiotic biosynthesis in the Streptomyces species, thereby leading to the discovery of new antibiotics.

This work is exciting for several reasons, Dr. Handelsman says. First, it confirms the long-standing but under- publicized theory that antibiotics evolved as signaling molecules rather than warfare molecules.

"This work is just one more piece in the puzzle of understanding not only what antibiotics are produced by bacteria … but also it gives a little bit more credence to the idea that perhaps many of these double as signal molecules either within species or between species," she says. "Looking for new signal molecules may be a way to look for new antibiotics."

Equally importantly, these researchers may have found new production pathways for some potentially important biological molecules. "When we find new pathways, one of the possible outcomes is using parts of those pathways to mix with either chemistry or biochemistry to create new compounds," Dr. Handelsman says.

Hope for Patients With NeuroAIDS

Neurological damage associated with HIV stopped

HIV ravages a patient’s brain long after highly active antiretroviral therapy has controlled the virus elsewhere in the body. Recently, researchers identified a receptor that the protein Tat uses to attack HIV-affected brain cells. By blocking that receptor, they were able to stop the damage.

"The pivotal finding in this study is the discovery that the HIV-1 protein Tat can cause abnormal signaling through the ryanodine receptor in neurons, causing both the unfolded protein response in the rough endoplasmic reticulum and dysfunction of mitochondria. [The result is] that both organelles lose their ability to manage calcium, a key second messenger in neuronal function and synaptic communication," said Harris Gelbard, MD, PhD, a neurologist at the University of Rochester Medical Center.

"This finding may provide a new approach to developing drugs that work at the level of the ryanodine receptor to reverse neurologic disease associated with HIV-1 infection of the brain. [It] is of crucial importance to a population that is aging with symptoms of AIDS kept in check by combination antiretroviral drugs."

This research also offers hope for diseases like Alzheimer’s and Parkinson’s, which have a molecular action similar to neuroAIDS, also known as AIDS dementia, Dr. Gelbard said.

Works Like a Virus

Tat works just like a virus, directly infecting nerve cells and causing cellular dysfunction through the ryanodine receptor. First, it renders the mitochondria defenseless against calcium level changes. Second, instead of killing the cell, Tat gives the endoplasmic reticulum a "tummy ache" by causing an unfolded protein response, said Dr. Gelbard.

"It was kind of a one-two punch that this protein is able to move directly into nerve cells and is able to pretty rapidly induce an unfolded protein response that makes the nerve cells sick, requires more energy," Gelbard said. "In response to that, the same receptor makes the mitochondria supply more energy at the expense of being able to buffer calcium, which in turn means that it’s less efficient at being able to send messages to nerves."

The researchers found that a single exposure had significant effects. "In addition to being able to infect nerves, [the protein] is also capable of infecting immune cells in a way that seems to be prolonged and only requires a single exposure," Dr. Gelbard said.

This study could have significant impact, another researcher noted. First, it confirms and builds on other observations of subcellular neuronal dysfunction in neuroAIDS—that is, mitochondrial and endoplasmic reticulum abnormalities, said William R. Tyor, MD, professor, departments of neurology and microbiology and immunology, Medical University of South Carolina, Charleston. "Assuming that the in vitro work on Tat accurately reflects what is happening in humans who have mitochondrial and endoplasmic reticulum dysfunction in the setting of HIV-associated dementia, then these observations could have significant impact," said Dr. Tyor.

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