In response to antibiotics, a gene regulation network found in the bacterium Acinetobacter baumannii acts to boost both virulence and antibiotic resistance. Edward Geisinger of Tufts University School of Medicine and colleagues present new insights into this system in a study published in PLOS Pathogens.
A. baumannii is a multi-drug resistant bacterium that spreads in hospitals around the world, causing serious infections such as pneumonia, wound infection, and sepsis. Previous research has shown that the bacterium's BfmRS system, a network of molecules that influence gene expression, enables it to build a protective capsule around itself in response to attack with antibiotics.
Despite the importance of BfmRS, its precise role in regulation of gene expression in the bacterium, and the resulting influence on the ability of A. baumannii to resist antibiotics and cause disease, have been unclear. In the new study, Geisinger and colleagues performed a series of experiments to clarify the role of BfmRS.
Using strains of A. baumannii that were genetically altered to either activate or wipe out the BfmRS stress response, the researchers showed that BfmRS enables lethal sepsis in mice. They also tested how these strains responded to antibiotic exposure, finding that the BfmRS stress response confers resistance to a wide variety of drugs.
The research team also showed that these effects are connected to the genetic influence of BfmRS, demonstrating through RNA sequencing experiments that it can reprogram gene expression throughout the A. baumannii genome. In particular, BfmRS controls a variety of genetic pathways involved in construction and integrity of multiple components of the cell envelope as well as cell division.
In a final experiment, the scientists showed that mutations to enhance antibiotic resistance could bypass the need for BfmRS in an A. baumannii strain in which BfmRS had been wiped out. These mutations also impacted processes that influence the cell envelope and division, highlighting the link between drug resistance and cell physiology.
Together, these findings show that BfmRS plays a central coordinating role in the intertwined ability of A. baumannii to resist antibiotics and boost virulence in response to them. This suggests that inhibition of BfmRS could serve as a potential strategy to combat A. baumannii.
"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 further explain. "These proteins control broad drug resistance and the potential to cause opportunistic disease, and center on processes that build and maintain the cell envelope."
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Citation: Geisinger E, Mortman NJ, Vargas-Cuebas G, Tai AK, Isberg RR (2018) A global regulatory system links virulence and antibiotic resistance to envelope homeostasis in Acinetobacter baumannii. PLoS Pathog 14(5): e1007030. https:/
Funding: The National Institute of Allergy and Infectious Diseases supported the work performed by RRI (01 AI124302, R21 AI128328), NJM (U01 AI124302), and EG (U01 AI124302 and F32 AI098358). The National Institute of General Medical Sciences supported the work performed by GV-C (R25 GM066567). HHMI also supported the work by RRI, EG, and GV-C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.