Slasher Molecule Rips Bacterial Membranes to Ribbons

Bacterial resistance is a major problem in even the best medical centers of the world. Bacteria are capable of evolving defenses against antibiotics almost as soon as they are introduced. Researchers are constantly seeking new approaches to the fight against pathogenic bacteria. This Newswise newsreport details the work of Gregory Tew and Zhan Chen, from UM Amherst and U Michigan, respectively.

The newly designed antimicrobial compound has a super-stiff backbone, an important structural decision, says Tew, noting that previously researchers focused on the arrangement of the side-chains that are attached to the backbone. The stiff spine yields a compound that has charges distributed in such a way that it is attracted to the water-lipid interface of the bacterial membrane, says Tew.

To test its ability to distinguish friend from foe, the researchers pitted the new compound against microbes such as E. coli and Staphylococcus aureus—the bacterium whose resistant strains plague hospitals—and against human red blood cells. The tests revealed that the new design is indeed both lethal and selective. While it slashed bacterial membranes with zeal, the compound left the human blood cells alone.

Many antibiotics attack a bacterium’s membrane-making machinery, not the membrane itself, says Tew. By taking a hint from nature and mimicking a class of molecules that goes right for the membrane, he hopes bacteria won’t be able to simply tweak their machinery to evade it. The new molecule has shown no propensity for inducing resistance compared to current antibiotics that attack bacteria through more classical routes, he says.

Gaining a better understanding of how these antibiotics work against the membrane will be essential to further improvements, says Tew. So he and Chen used sum frequency generation (SFG) vibrational spectroscopy—a technique that uses lasers and is typically employed by chemists for identifying molecules at surfaces—to further explore the antibiotic-membrane interaction. Tew and Chen have harnessed SFG to explore which molecules pack the strongest antimicrobial punch and how this punch is delivered at the molecular level.

....Using SFG lets the researchers watch a potential antibiotic at work—and at concentrations that are meaningful, says Tew. By combining the SFG data with lab experiments on a compound’s bacteria-inhibiting abilities and tests that look at how much cell leakage occurs, researchers will be able to learn more about the molecular interactions governing this antimicrobial activity, he says.

“Being able to see how these molecules interact with the membrane at the molecular level in real-time will prove invaluable,” says Tew. “This will let us build much better models of how these novel antibiotics interact with membranes—if we understand that, we can build drugs that are more effective and less toxic.” Source.

Although bacteria are able to exchange genetic material with each other--transferring antibiotic resistance almost instantly--there is a limit to the cleverness of microbes. Humans are able to continue probing the molecular mechanisms of bacteria, at ever greater depths of complexity. Antibiotics were an accidental discovery, and not particularly clever on the part of humans. Bacteria have been dealing with antibiotics produced by plants and other microorganisms for hundreds of millions of years.

New approaches to defeating pathogenic bacteria will be novel--evolution will not have prepared bacteria for what is coming.