Research Sheds Light on Mechanism That Leads to Drug-Resistant ‘Superbugs’

Organisms shed essential cell-wall molecules

Drug-resistant organisms––commonly known as “superbugs––are a growing public health threat because last-resort therapeutics are failing. Researchers at the University of Georgia are the first to examine multiple strains of one of the most dangerous superbugs and a last-resort antibiotic used to treat it. The findings deepen current understanding of how pathogens adapt to protect themselves from antibiotics and will enable researchers to develop therapeutics aimed at evading this mechanism, according to the investigators.

The new study was published online in the Proceedings of the National Academy of Sciences.

Dr. M. Stephen Trent and his team found that several strains of the gram-negative bacterium Acinetobacter baumannii mutate into drug-resistant bacteria by shedding a layer of their outermost membrane in response to exposure to colistin (polymyxin E), a decades-old antibiotic. The bacterium inactivates the production of an essential molecule to which colistin is designed to bind, which prevents the drug from entering the cell to neutralize the infection—suggesting that the bacterium has adapted a novel mechanism to protect itself.

Previous research isolated this behavior to a single strain of A. baumannii, but the new study is the first to track multiple strains and determine that colistin-resistance is a response to treatment. Trent and his team chose colistin for the study because it represents the “end of the line” for bacterial infection treatment options. The investigators wanted to understand how gram-negative bacteria, such as A. baumannii, can survive without lipopolysaccharides (LPS)––essential cell-wall molecules.

“Bacteria are phenomenally adaptive, and if the antibiotic can’t bind to or enter the bacterium, it is not effective,” Trent said. The theory is that if scientists can better understand how bacteria become superbugs, they can develop effective antibiotics to combat the bugs’ resistant mechanisms.

A. baumannii, also known as “Iraqibacter” because soldiers acquired infections from the organism in Iraq and brought them back to the U.S., is particularly difficult to kill because of its ability to quickly acquire multidrug resistance. The organism often wreaks havoc in hospitals, where it jumps quickly between patients and hospital personnel.

For a long time, colistin resistance was rare, but it has become more prevalent. Colistin has been used since the 1950s, but because of its adverse effects, it is used only as a last resort. Because the antibiotic’s use is not widespread, most bacteria are susceptible to it. Therefore, when colistin proves ineffective in treating an infection, health care providers are out of options.

Data from the new study indicated that half of the A. baumannii strains exposed to colistin shed their protective LPS layers. The researchers also found that not all A. baumannii strains can survive without this layer. While some strains thrived without their LPS armor and successfully resisted treatment with colistin, other strains did not. After the antibiotic left patients’ systems, the strains that survived without LPS produced a new protective layer.

“In effect, the bacteria can quickly adapt to any situation, making them even more dangerous,” Trent said.

Sources: University of Georgia; September 28, 2016; and PNAS; September 28, 2016.