Scientists Resurrect 3-Billion-Year-Old Antibiotic-Resistance Proteins

A team of researchers from the Georgia Institute of Technology in Atlanta, the Universidad de Granada and Instituto Andaluz de Ciencias de la Tierra, Spain, has reported about the laboratory resurrection of several 2-3-billion-year-old proteins that are ancient ancestors of the enzymes that enable today’s antibiotic-resistant bacteria to shrug off huge doses of penicillins, cephalosporins and other drugs.

Structural comparison of the TEM-1 β-lactamase, the most commonly encountered beta-lactamase in gram-negative bacteria, shown in green, and two resurrected β-lactamases, shown in red and blue. Arrows point to structural differences (Valeria A. Risso et al)

Structural comparison of the TEM-1 β-lactamase, the most commonly encountered beta-lactamase in gram-negative bacteria, shown in green, and two resurrected β-lactamases, shown in red and blue. Arrows point to structural differences (Valeria A. Risso et al)

The breakthrough, described in the Journal of the American Chemical Society, opens the door to a scientific ‘replay’ of the evolution of antibiotic resistance with an eye to finding new ways to cope with the problem.

“Antibiotic resistance existed long before Alexander Fleming discovered the first antibiotic in 1928. Genes that contain instructions for making the proteins responsible for antibiotic resistance have been found in 30,000-year-old permafrost sediment and other ancient sites,” the scientists said.

Their study focused on the so-called beta-lactamases, enzymes responsible for resistance to the family of antibiotics that includes penicillin, which scientists believe originated billions of years ago.

The scientists used laboratory and statistical techniques to reconstruct the sequences of beta-lactamase proteins dating to Precambrian times, 2-3 billion years ago. They also synthesized the inferred ancestral enzymes and conducted studies on their stability, structure and function.

“The availability of laboratory resurrections of Precambrian beta-lactamases opens up new possibilities in the study of the emergence of antibiotic resistance,” they wrote in the paper.

“For instance, it should now be possible to perform laboratory replays of the molecular tape of lactamase evolution and use such replays to probe the molecular determinants of the efficiency of lactamases to adapt to different types of antibiotics.”

“The extreme stability and catalytic features displayed by the 2-3-billion-year-old lactamases suggest that resurrected Precambrian proteins have utility for the biotechnology industry.”

______

Bibliographic information: Valeria A. Risso et al. 2013. Hyperstability and Substrate Promiscuity in Laboratory Resurrections of Precambrian β-Lactamases. J. Am. Chem. Soc., 135 (8), pp. 2899–2902; doi: 10.1021/ja311630a