IIT Roorkee researchers have identified the RNA protein Hfq as a potential drug target. Once the Hfq gene is removed, the Acinetobacter baumannii bacteria become less virulent, more susceptible to environmental stress, and survival under desiccation is compromised. Targeting the virulence of the bacteria opens up a new opportunity to develop more effective drugs.
Researchers at Indian Institute of Technology (IIT) Roorkee have identified a protein (Hfq) in Acinetobacter baumannii bacteria that can be a potential drug target. The Hfq protein plays an important role in metabolism, drug resistance, stress tolerance and virulence. The protein stabilises the interaction of small RNA with its target mRNA molecules.
The A. baumannii bacteria are resistant to several antibiotics. They are one of the major causes of hospital-borne infections. They also have the unique ability to survive in dry and desiccated conditions for extended periods thus helping the bacteria to spread.
While most Gram-negative bacteria have Hfq protein, the protein is particularly long in the case of A. baumannii. For instance, in E. coli, the length of the Hfq protein is only about 100 amino acids while there are 168 amino acids in the case of A. baumannii bacteria. The end of the Hfq protein, called the C-terminus, is what is particularly long in A. baumannii. While another study had reported that the extra length of the C-terminus may not be significant in another bacteria belonging to the same family as A. baumannii, the IIT team found evidence to the contrary.
The team led by Prof. Ranjana Pathania from the Institute’s Department of Biotechnology found that when the Hfq gene was removed (knocked out), the bacteria became susceptible to environmental stress, showed stunted growth, survival under desiccation was compromised, and the ability to form biofilm was reduced. “But most importantly, the virulence of the bacteria was significantly reduced in mice model infected with the mutant bacteria,” says Prof. Pathania. The results of the study were recently published in The Journal of Biological Chemistry.
Targeting the virulence of the bacteria is a rather new concept which promises drugs that don’t lead to rapid generation of resistance.
To reconfirm the role of the extra length of Hfq protein, the researchers complemented or added the full length of the protein and also Hfq protein of different lengths (66, 72 and 92 amino acids). “While the full length of the complemented protein could restore all the functions and processes, including virulence, the Hfq protein lacking the C-terminus tail could not restore the functions of the protein. So it became apparent that the C-terminus tail is important,” says Prof. Pathania.
The resistance to two commonly used antibiotics reduced two-fold when the bacteria lacked the Hfq gene but the resistance increased nearly four-fold in the case of another antibiotic. “We are currently studying the mechanism by which the resistance increases in the case of the other drug (Meropenem),” she says.
More than the gene’s role in altering drug resistance, the researchers are thrilled at how removing the Hfq gene causes the bacteria to lose its ability to cause disease and the growth getting compromised. “Targeting the virulence of the bacteria is a rather new concept which promises drugs that don’t lead to rapid generation of resistance. Identification of Hfq as a virulence factor in the bacteria opens up a new opportunity to develop more effective drugs,” she says.
“Since the Hfq gene controls multiple pathways in the bacteria, it will be difficult for the bacteria to develop resistance against any drug that targets this gene,” says Prof. Pathania.