Enzyme's Structure Yields Blueprint For Antibiotic Resistance

August 21, 1998

August 21, 1998—Starting with the structure of a common bacterial enzyme, a team of investigators from the Howard Hughes Medical Institute at The Rockefeller University has unlocked the structural secrets at the heart of some of life's most important biological processes.

Using x-ray crystallography, HHMI investigator Stephen K. Burley and his colleagues, working with Alex Vassilev, Yasutaka Makino and Yoshihiro Nakatani of the National Institute of Child Health and Human Development, have generated the three-dimensional molecular structure of a common enzyme, known as aminoglycoside 3-N-acetyltransferase, from the bacterium Serratia marcescens. The research is reported in the August 21, 1998, issue of the journal Cell.

According to Burley, this work has far-reaching repercussions because the bacterial enzyme's structure is shared by a superfamily of at least 150 enzymes present in every kingdom of life. Across the members of this family, says Burley, minor differences on the surfaces of the molecules generate small changes in structure, allowing them to perform a variety of biological functions.

The HHMI team determined that the bacterial enzyme's structure resembles "a cupped right hand wrapped around a cylinder." Named in part for its function, the enzyme promotes the transfer of an acetyl group from a donor molecule to a recipient molecule. "The three-dimensional structure shows us how the enzyme positions both the donor and the recipient so that the transfer can occur," Burley says.

Using a technique called "threading," Burley's team, which included Rockefeller scientists Eva Wolf and Andrej Sali, used the structure of the single enzyme they discerned to examine other members of the family of enzymes without actually having to complete x-ray crystallography on each complex. "Essentially, we thread the amino acid sequence of the unknown structures through the structure of the protein we do know and ask, 'Is it a good fit?'" Burley says. Using this technique, the researchers determined that all 150 highly conserved enzymes share the same basic structure.

Three closely related member of the acetyltransferase superfamily exist in a growing number of bacteria and they can affect humans in a potentially life-threatening manner. These enzymes transfer an acetyl group to compounds known as aminoglycosides-widely prescribed antibiotics that include gentamicin, tobramycin and netilmicin.

"The transfer inactivates these antibiotics, making them ineffective. This is an example of emerging antibiotic resistance at work," says Burley. "Now that we know the structure of the enzymes, it may become possible to design a drug that can be given along with the antibiotic. A drug that blocks the enzymes could prevent the antibiotic from being inactivated." There is precedence for such a drug, Burley says, pointing to augmentin, which blocks the part of the enzyme that inactivates the antibiotic penicillin.

Other important acetyltransferases abound. One enzyme with the same fundamental structure is responsible for the final chemical step in synthesizing a neurotransmitter important in the control of mood, depression and anxiety. In another incarnation, a structurally similar enzyme acts as a switch that frees DNA to become active and begin expressing messenger RNA. Such widespread biological activity gives the discovery importance for a wide range of investigations.

Discerning the common structure of such a large family of enzymes also provides an important clue to understand how proteins accomplish life's functions. Burley explains that although there are some 100,000 human genes, they produce only about 2,000 basic protein structures. Slightly different surfaces give the proteins their unique chemical properties and abilities, but in many cases, their basic structures are shared. "We now know one more of the fundamental structures," Burley says.

Howard Hughes Medical Institute

Related Antibiotic Articles from Brightsurf:

Pollution linked to antibiotic resistance
Antibiotic resistance is an increasing health problem, but new research suggests it is not only caused by the overuse of antibiotics.

Antibiotic resistance and the need for personalized treatments
Scientists have discovered that the microbiota of each individual determines the maintenance of antibiotic resistant bacteria in the gut: whereas in some individuals resistant bacteria are quickly eliminated, in others they are not.

Artificial intelligence yields new antibiotic
Using a machine-learning algorithm, MIT researchers have identified a powerful new antibiotic compound.

From cancer medication to antibiotic
Antibiotic-resistant bacteria are increasingly the source of deadly infections. A team of scientists from the Technical University of Munich (TUM) and the Helmholtz Center for Infection Research (HZI) in Braunschweig have now modified an approved cancer drug to develop an active agent against multidrug-resistant pathogens.

Up to two-fifths of antibiotic prescriptions in the US could be inappropriate
As much as two fifths (43%) of antibiotic prescriptions in the United States could be inappropriate, warn researchers in a study published by The BMJ today.

New understanding of antibiotic synthesis
Researchers at McGill University's Faculty of Medicine have made important strides in understanding the functioning of enzymes that play an integral role in the production of antibiotics and other therapeutics.

Cause of antibiotic resistance identified
Bacteria can change form in human body, hiding the cell wall inside themselves to avoid detection.

Cannabidiol is a powerful new antibiotic
New research has found that Cannnabidiol is active against Gram-positive bacteria, including those responsible for many serious infections (such as Staphyloccocus aureus and Streptococcus pneumoniae), with potency similar to that of established antibiotics such as vancomycin or daptomycin.

New approaches cut inappropriate antibiotic use by over 30%
A UC Davis study of nine emergency departments and urgent care centers in California and Colorado found educating physicians and patients about safe antibiotic use can cut overuse by one-third.

How certain antibiotic combinations could defeat 'superbugs'
In hospitalized patients with bacterial infections, heteroresistance is more widespread than previously appreciated.

Read More: Antibiotic News and Antibiotic Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.