The deadly hospital pathogen Acinetobacter baumannii can live up to a year on a hospital wall without food and water. Then, when it infects a weakened patient, it becomes resistant to antibiotics as well as the body’s built-in infection-fighting response. It is recognized by the World Health Organization (WHO) as one of the three major pathogens that desperately need new antibiotic treatments.
Now, an international team led by Macquarie University researchers Dr. Ram Maharjan and Associate Professor Amy Cain has discovered how superbugs can survive harsh environments and then recover, causing deadly infections. They found one protein that acts as a master regulator. When the protein is damaged, the insect loses its superpowers allowing it to be controlled, in a laboratory environment. Research published in Nucleic acid research.
“We hope our paper will encourage researchers around the world to refocus on drug development to fight these superbugs, which are circulating in the world’s hospitals, killing already vulnerable people in intensive care units and other high-risk areas,” says Associate Professor Cain, Senior authors on paper.
Six superbugs are scaring global health officials. Escherichia coli, Klebsiella pneumoniae and other Gram-negative bacteria have common pathways that confer resistance to antibiotics. A. baumannii are different. It is particularly difficult, and is one of the most resistant pathogens we encounter. Oddly enough, we don’t know much about how we get infected.
A breakthrough in the search challenge
“In the lab, we can see that this pathogen is very tough. Other researchers have shown that you could dry the insect for a year, and when they added water, it was still able to infect mice,” says Professor Cain.
“The problem was that A. baumannii is relatively new to the scene, emerging as a problem in hospitals in the 1980s. It is difficult to genetically manipulate using the existing molecular biology toolkit. It usually only infects patients, but it is so highly resistant to antibiotics that it is very difficult to treat and difficult to research.” Safely. So, we don’t know much about it. We don’t know where it came from, nor how it became so resistant and resilient. Now, thanks to this on paper, we know how it handles stress.”
Amy and her colleagues realized about five years ago that they could make a difference by trying to understand the basic biology of A. baumannii. This led to a significant investment by Macquarie University in research, in biocontainment laboratories for personnel safety, and in an ethical animal model using moth larvae. Research efforts have been strongly supported by the Australian Council and the National Health and Medical Research Council.
During infection, our cells fight back by dumping or starving the bacteria of essential minerals like copper and zinc. A. baumannii contains powerful drug pumps that push antibiotics, metals, and other threats out of the cell.
“By studying how this bug deals with infection stress, we found an important uncharacterized regulatory protein (DksA). When we disrupt this protein, it leads to changes in about 20 percent of the insect’s genome and breaks the pumping system,” says Dr. Ram Maharjan, researcher at Macquarie University and senior author on the paper.
This protein not only controls stress response, but also virulence. baumannii normally circulates in the blood, but our perturbation also caused it to be completely undetectable in the blood of both Galleria mellonella and mice. It also becomes very sticky and harmless to the organs.
Ram P Maharjan et al, DksA is a conserved master regulator of the stress response in Acinetobacter baumannii, Nucleic acid research (2023). DOI: 10.1093/nar/gkad341
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