Ancient enzymes conferring antibiotic resistance re-created in the lab

March 4, 2013 § 2 Comments

Structure of a Streptomyces albus beta-lactamase (http://en.wikipedia.org/wiki/File:PDB_1bsg_EBI.jpg)

Structure of a Streptomyces albus beta-lactamase (http://en.wikipedia.org/wiki/File:PDB_1bsg_EBI.jpg)

Resistance against antibiotics, such as penicillin and cephalosporins, are haunting many hospitals and clinical practices. In a recent paper  in the Journal of the American Chemical Society, researchers reported that they made laboratory versions of the ancient ancestors of the enzymes that lead to antibiotic resistance. By studying the ancient forefathers of these enzymes, researchers hope to understand how modern antibiotic resistance evolved and figure out new ways to deal with it. “Antibiotic-resistant organisms cause thousands of human deaths every year. Anything new we can learn about antibiotic resistance may be potentially useful in coping with this problem,” says Jose Sanchez-Ruiz at the University of Granada in Spain, one of the study’s coauthors.

Antibiotic resistance isn’t a modern phenomenon that only arose in the face of clinical antibiotic use in the past 60 years. Bacteria have been toting around enzymes to disarm antibiotics for millenia. Indeed, genes for antibiotic resistance have been found in 30,000-year-old permafrost sediment and in places largely untouched by human activity, such as remote Alaskan soil and the bottom of the Pacific Ocean.

The class of enzymes that render drugs like penicillin useless are called beta-lactamases. The question is whether current pathogenic bacteria are simply recruiting, or improving upon, enzymes like beta-lactamases or other molecules that confer resistance in natural environments.

The permafrost sediment study dated antibiotic resistance as 30,000 years old. “But we knew that it is actually much older than just 30,000 years, because the resistance enzyme beta-lactamase is widely distributed throughout the bacterial domain of life. Phylogenetic analysis places its origin at about 2 to 3 billion years ago,” says Valeria Risso, also at the University of Granada.

To figure out how these enzymes functioned way back when, Risso and Sanchez-Ruiz, along with Eric Gaucher at the Georgia Institute of Technology, used bioinformatics tools to reconstruct ancestral lactamase sequences corresponding to the Precambrian nodes in the bacterial evolutionary trees. They then used molecular biology approaches to make the corresponding proteins in the laboratory and studied their structure, stability and function.

From their analyses, the investigators found that the Precambrian beta-lactamases were highly stable and promiscuous, with the ability to degrate a variety of antibiotics. This finding has biotechnological applications because highly stable and promiscuous enzymes are “in the top of the wish list of any protein engineer,” says Sanchez-Ruiz.

The investigators also say that when a microorganism develops resistance toward a drug,  it is repeating an adaptation process that likely took place in natural environments for several billion years. “The availability of resurrected Precambrian lactamases opens up new possibilities to understand such evolutionary adaptations and may therefore provide useful information to cope with modern antiobiotic-resistance problem,” says Risso.

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