IIT Hyderabad finds a chink in E. coli armour

e-coli-optimized
The IIT Hyderabad team led by Dr. Thenmalarchelvi Rathinavelan is look at different strategies to make E. coli vulnerable to attack by the host’s immune system.

Researchers at the Indian Institute of Technology, Hyderabad (IIT-H) have made a promising start to render E. coli  bacteria more susceptible to host immune response. The researchers have found a potential way of preventing the bacterial surface-associated polysaccharide — capsular polysaccharide (CPS) or K antigen — from attaching on the surface membrane and forming a protective encapsulation of the bacteria, thus making the E. coli  vulnerable to attack by the host’s immune system.

The CPS is synthesised by the bacteria and exported to the surface to offer protection by evading the host immune response. Surface-association of CPS also offers impermeability to antibiotics, thus establishing infection in the host. Certain surface-associated bacterial proteins help in the attachment of CPS on the bacterial surface.

“If you know how the CPS is attached to the bacteria’s membrane protein then we can design a drug that can go and bind to the protein and prevent the CPS from getting attached to the bacterial surface,” says Dr. Thenmalarchelvi Rathinavelan from the Department of Biotechnology, IIT Hyderabad.

optimal concentration of CPS should be maintained, and this is achieved through water conduction.“The CPS is not the same in all the E. coli strains but varies. In all, there are 80 such capsular polysaccharides. We have modelled the 3D structures and developed an organised repository of 72 CPS varieties,” says Dr. Rathinavelan the corresponding author of a paper published in the journal Nucleic Acids Research. “The database is called EK3D [E. coli K antigen 3-Dimensional Structure Database].” The database can facilitate the development of efficacious drugs against E. coli infections.

After developing the models of 72 CPS structures, the team led by Dr. Rathinavelan has proposed the binding site of CPS on the membrane protein surface. The results were published in June 2016 in the journal Scientific Reports.

Dual role

“The bacterial membrane protein has a dual role. Besides facilitating the binding of CPS, it also conducts water from inside the bacteria to outside and from outside to inside to maintain the osmotic pressure,” she says. The team has identified five water diffusion points (two inside and three outside the bacteria).

The osmotic pressure becomes high when the amount of CPS is more on the surface. Under such circumstances, water is transported from inside the bacteria to outside to dilute and spread the concentration of CPS and avoid the rupturing of the cell. This also helps in keeping the CPS in a hydrated condition and prevents further accumulation of CPS on the surface. But when the concentration of CPS is less on the surface the pressure inside the bacteria reduces. Water is transported from outside to inside the bacteria to normalise the pressure.

“Basically, optimal concentration of CPS should be maintained, and this is achieved through water conduction, called osmoregulation,” Dr. Rathinavelan says.

The team is now working on proving what they had observed — the attachment region of CPS to the membrane protein and the dual role of the protein in conducting water.

“If we can alter the water conduction property of the protein we can control the accumulation of CPS on bacterial surface and make the bacteria accessible to the host immune system,” she says. “Alternatively, if we block the CPS binding site with a drug molecule then CPS cannot bind to the bacterial membrane. The site where the protein binds to the membrane can also be targeted. These strategies may pave the way for tackling emergence of multi-drug resistance in Gram-negative bacteria.”

Published in The Hindu on October 9, 2016

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