Research produces new antibiotic-resistant to bacterial resistance - Video

Researchers at the University of Illinois Chicago and Harvard University have created an antibiotic that could provide medicine with a fresh tool to combat drug-resistant bacteria and their associated diseases.

Published in Nature Chemical Biology, the antibiotic, Cresomycin, effectively suppresses pathogenic bacteria that have become resistant to many commonly prescribed antimicrobial drugs.

The UIC scientists focused on how many antibiotics interact with a common cellular target – the ribosome – and how drug-resistant bacteria modify their ribosomes to defend themselves. Their critical insights into cellular mechanisms and structure aided Harvard researchers in designing and synthesizing new drugs, including the development of the new antibiotic.

More than half of all antibiotics inhibit growth of pathogenic bacteria by interfering with their protein biosynthesis – a complex process catalyzed by the ribosome. Antibiotics bind to bacterial ribosomes and disrupt this protein-manufacturing process, causing bacterial invaders to die.But many bacterial species evolved simple defences against this attack. In one defense, they interfere with antibiotic activity by adding a single methyl group of one carbon and three hydrogen atoms to their ribosomes.

By using a method called X-ray crystallography to visualize drug-resistant ribosomes with nearly atomic precision, scientists discovered two defensive tactics. The methyl group, they found, physically blocks the binding site, but it also changes the shape of the ribosome’s inner “guts,” further disrupting antibiotic activity.

“By determining the actual structure of antibiotics interacting with two types of drug-resistant ribosomes, we saw what could not have been predicted by the available structural data or by computer modelling,” said Yury Polikanov, associate professor of biological sciences at UIC, and colleagues at Harvard.

Cresomycinis synthetic. It’s preorganized to avoid the methyl-group interference and attach strongly to ribosomes, disrupting their function. This process involves locking the drug into a shape that is pre-optimized to bind to the ribosome, which helps it get around bacterial defenses.

“It simply binds to the ribosomes and acts as if it doesn’t care whether there was this methylation or not,” Polikanov said. “It overcomes several of the most common types of drug resistance easily.”

“Without the structures, we would be blind in terms of how these drugs bind and act upon modified drug-resistant ribosomes. The structures that we determined provided fundamental insight into the molecular mechanisms that allow these drugs to evade the resistance.” concluded Polikanov.

Reference: DOI: 10.1126/science.adk8013