Newswise — The lethal hospital germ Acinetobacter baumannii can survive for a year on a hospital wall without nourishment and hydration. Subsequently, when it invades a susceptible individual, it withstands antibiotics along with the body's inherent infection-fighting reaction. The World Health Organization (WHO) acknowledges it as one of the three major germs requiring urgent development of novel antibiotic treatments.

Presently, a global group, spearheaded by Dr. Ram Maharjan and Associate Professor Amy Cain from Macquarie University, has unveiled the survival mechanism of this superbug in extreme conditions and its subsequent resurgence, leading to fatal infections. They have identified a sole protein that functions as a supreme controller. When this protein is impaired, the bug forfeits its exceptional abilities, rendering it manageable within a laboratory environment. The findings of this research have been published in Nucleic Acids Research.

"By publishing our paper, we aim to inspire researchers worldwide to redirect their efforts towards the development of medications to combat this superbug. It is rapidly spreading within hospitals across the globe, claiming the lives of individuals who are already vulnerable in intensive care units and other high-risk zones," expressed Associate Professor Cain, the senior author of the study.

Global health officials are deeply concerned about six superbugs that pose a significant threat. Among them are E. coli, Klebsiella pneumoniae, and other gram-negative bacteria, which share similar routes that confer antibiotic resistance. However, A. baumannii sets itself apart. It exhibits exceptional resilience and stands as one of the most formidable pathogens we face. Interestingly, our understanding of its infection mechanism remains limited.

Breakthrough in a research challenge

"Within the laboratory setting, we have observed the remarkable resilience of this pathogen. Previous studies have demonstrated that even after desiccating the bug for an entire year, it retained its infectivity when water was reintroduced, successfully infecting mice," stated Associate Professor Cain.

"The challenge we have faced with A. baumannii is its relatively recent emergence as a hospital-acquired problem in the 1980s. Moreover, its genetic manipulation has proven difficult using the current molecular biology tools. Typically, it primarily infects individuals who are already ill, but its exceptional resistance to antibiotics makes treatment incredibly challenging and researching it safely becomes problematic. Consequently, our knowledge about this pathogen has been limited. We have lacked information regarding its origin, as well as the factors contributing to its resistance and resilience. Fortunately, this paper sheds light on how it copes with stress, providing a significant breakthrough in our understanding," explained the significance of the research.

Around five years ago, Associate Professor Amy and her colleagues recognized the potential impact they could make by delving into the fundamental biology of A. baumannii. This realization prompted Macquarie University to make a substantial investment in research, including the establishment of biocontainment laboratories to ensure staff safety. Additionally, an ethical animal model using moth caterpillars was developed to further advance the study. The research endeavor received significant support from the Australian Council and the National Health and Medical Research Council, underscoring the importance and backing for this critical work.

"We aspire that our paper will serve as a catalyst, inspiring researchers worldwide to redirect their efforts towards the development of pharmaceutical interventions aimed at combating this relentless superbug, which continues to spread within hospitals across the globe," expressed the researchers.

In response to infection, our cells employ various defense mechanisms, including the strategy of depriving bacteria of vital metals like copper and zinc or inundating them with these metals. However, A. baumannii possesses robust drug pumps that actively expel antibiotics, metals, and other hazardous substances from within the cell. This ability enhances its resilience and contributes to its resistance against antimicrobial agents and the host's immune system.

"Through our investigation into the mechanisms employed by this pathogen to cope with infection-related stressors, we have discovered a crucial yet uncharacterized regulatory protein known as DksA," explained Dr. Ram Maharjan, a researcher at Macquarie University and the lead author of the paper. "When we disrupt the function of this protein, it induces alterations in approximately 20 percent of the bug's genome and impairs its pumping system, rendering it less formidable," Dr. Maharjan added.

In addition to its role in stress response, the identified protein also governs the virulence of A. baumannii. Normally, this pathogen spreads through the bloodstream, but when we disrupted the protein, it became entirely undetectable in the blood of both Galleria mellonella (moth caterpillars) and mice. Interestingly, the disrupted strain exhibited a unique characteristic of enhanced stickiness, allowing it to harmlessly adhere to organs. This finding suggests that the protein not only influences the pathogen's ability to cause infection but also affects its dissemination and interaction with host tissues.

The new paper builds on a discovery earlier this year also led by Macquarie researchers that showed that K. pneumoniae and A. baumannii work together to avoid antibiotics.

Associate Professor Amy Cain is an Australian Research Council Future Fellow and researchers antimicrobial resistance in the School of Natural Sciences.

Journal Link: Nucleic Acids Research