E. coli persists against antibiotics through HipA-induce...(nase inhibitors will bind to and block H...),Health

Persistence is common in "biofilms," bacterial colonies that become attached to a surface in a supportive matrix. Drug-resistant biofilms cause about 60 percent of infections in the developed world, the researchers note.

Overexpression of HipA previously had been associated with cell dormancy and bacterial persistence. Evidence had pointed to kinase activity.

Schumacher, Brennan and colleagues demonstrated the molecular details of HipA's role in multidrug tolerance and HipB's role keeping HipA under wraps in a series of experiments:

• Using X-ray crystallography to determine and then compare the structures of several HipA complexes, they showed that HipA has a serine/threonine protein kinase fold and that it binds tightly to adenosine triphosphate (ATP), a common characteristic of kinases. Phosphorylation occurs when an enzyme binds to both ATP and to its target protein.
• Assays of candidate proteins to identify a target for HipA found that EF-Tu interacts strongly with HipA in the presence of ATP. EF-Tu is the most abundant protein in E.coli and plays an essential role in protein synthesis.
• Subsequent experiments and structural analysis of a HipA/EF-Tu peptide complex indicated that HipA phosphorylates EF-Tu, freezing up the bacteria's protein-making machinery and inducing dormancy.
• To analyze how HipB normally prevents HipA's function, the team solved the structure of the HipB/DNA/HipA complex. HipB tightly binds two HipA molecules in a sandwich-like structure.
• HipB does not block HipA's active site, but inactivates it by forcing it into an "open" position. "Proteins move a lot to function, they open and close - think of a clam she
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