Insights into gene network could expose new targets for drug-resistant infections

A decade ago, the bacterium Acinetobacter baumannii was identified as one of the six most common and serious multidrug-resistant pathogens, largely because of its propensity to spread in hospitals, causing infections like sepsis and pneumonia. Scientists have long known that A. baumannii resists treatment with antibiotics by building a capsule to protect itself—they just haven’t been able to figure out exactly how the bug achieves this feat.

A team at Tufts University School of Medicine has published new research that explains how A. baumannii builds this protective coating, allowing it to become more virulent as it continues to evade destruction from antibiotics. The key is a network of molecules that turn specific genes on and off.

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The molecular network that the Tufts researchers focused on is called BfmRS. First they genetically altered strains of the bacteria to either activate or cripple the network. When they activated it, they found that BfmRS caused sepsis in mice that was widely resistant to antibiotics.

Then they used RNA sequencing to reprogram A. baumannii’s genes, and in so doing discovered that BfmRS controls genes that influence cell division and the protective envelope around cells, according to a statement.

But the Tufts team also discovered mutations that allowed the bacterium to resist antibiotics without help from BfmRS. The researchers made that discovery by studying one strain of A. baumannii in which BfmRS was deleted. They published their findings in the journal PLOS Pathogens.

The effort to combat multidrug-resistant infections has pulled in scientists from both academia and industry. Among the players are Macrolide Pharma, which raised $20 million in funding and recruited Novartis veteran Mahesh Karande as it CEO in April. In March, Genentech announced it identified an enzyme on the surface of drug-resistant gram-negative bacteria that can be targeted with an antibody, weakening the outer membrane just enough to kill the bug.

The research at Tufts is partially supported by the National Institutes of Health’s National Institute of Allergy and Infectious Diseases, which has been funding a range of research projects under the National Action Plan for Combating Antiobiotic-Resistant Bacteria, launched in 2015.

"We revealed that a single two-protein system controls a global network of proteins that is critical for making A. baumannii a threat," the authors said in their paper. They believe BfmRS could be directly targeted to battle drug-resistant infections.