A team of scientists, led by researchers from the Howard Hughes Medical Institute (HHMI) at The Rockefeller University, has determined the three-dimensional structure of an enzyme responsible for resistance of certain bacteria to the antibiotic gentamicin. The structure, reported in the August 21 Cell, is the first for this family of antibiotics and presents a possible target for designing drugs to thwart resistance.
"Our structure of this antibiotic-resistance enzyme reveals how remarkably simple proteins can present life-threatening problems for critically ill patients," says senior author Stephen K. Burley, M.D., D.Phil., Richard M. and Isabel P. Furlaud Professor and head of the Laboratory of Molecular Biophysics at Rockefeller. Burley, an HHMI investigator, also directs the university's Center for Biochemistry and Structural Biology.
The enzyme belongs to a family of proteins called aminoglycoside N-acetyltransferases (AATs). AATs catalyze the addition of molecules called acetyl groups to aminoglycoside antibiotics such as gentamicin, tobramycin and netilmicin, which are commonly directed against certain bacteria that are responsible for hospital-acquired infections in people with compromised immune systems. Bacteria acquire AATs and become resistant to these antibiotics through overuse.
The enzyme's structure resembles a cupped right hand wrapped around a cylinder. The cavity produced by the cupped hand, dubbed the gentamicin-binding slot by the researchers, presents a possible target for drugs aimed at thwarting antibiotic resistance.
"We think that this narrow cleft acts as the binding site for gentamicin and holds it in place," says Burley. "When the acetyl group is transferred to the protein, the gentamicin flies off.
These findings open the door for the design of drugs that would inhibit the action of AAT.
Burley's co-authors on the paper are Eva Wolf, Ph.D., and Andrej Sali, Ph.D., at Rockefeller and Alex Vassilev, Ph.D., Yasutaka Makino, Ph.D., and Yoshiro Nakatani, Ph.D., at the National Institute of Child Health and Human Development, National Institutes of Health (NIH).
The work was supported in part by The Rockefeller University, Richard M. and Isabel P. Furlaud, the National Institute of General Medical Sciences at NIH and the National Science Foundation. Wolf is a Deutscher Akademischer Austauschdienst Fellow and Sali is a Sinsheimer Scholar and an Alfred P. Sloan Research Fellow.
Rockefeller began in 1901 as The Rockefeller Institute for Medical Research, the first U.S. biomedical research center. Rockefeller faculty members have made significant achievements, including the discovery that DNA is the carrier of genetic information and the launching of the scientific field of modern cell biology. The university has ties to 19 Nobel laureates, four of whom are on campus, including the president, Torsten N. Wiesel, M.D., who received the prize in 1981.
Journal
Cell