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Drug resistance: 'Baby steps' can pay off big
Date:1/9/2013

ld accurately predict how specific mutations would affect E. coli resistance, Shamoo's team examined a gene called TetX2. The gene encodes an enzyme that inactivates the antibiotic minocycline. The researchers looked at the most likely mutations of the gene and found seven that led to increased antibiotic resistance. They then spent two years amassing a catalog of basic biochemical measurements for each mutant.

"If this organism were a car, then these enzymatic measurements would be the equivalent of things like the cubic displacement of the engine, the torque and so on," Shamoo said. "These are measurable variables, but by themselves they won't tell you the car's top speed or how fast it can accelerate from 0 to 60 (miles per hour)."

By measuring the performance improvements from each of the seven TetX2 mutants, the group was able to build a mathematical formula that accurately correlated the E. coli resistance with enzyme performance. To test the formula, the team measured the resistance of a new family of mutants and used the formula to calculate their enzyme performance metrics.

"Using the car analogy again, it's like we took one car and measured its top speed and acceleration using seven different engines," Shamoo said. "Then, we took the same car with an unknown engine and showed that we didn't have to open the hood and look to tell what kind of engine it had. We could tell that strictly by knowing its top speed and acceleration." By knowing how the car with the unknown engine performed on the race track, we could describe the engine without ever popping the hood and vice versa.

Shamoo said the research could lead to faster screening methods for resistant strains of bacteria, but the most immediate benefit is an improved understanding of how resistance develops.

"An example of that is this finding about the small steps," he said. "That was unexpected, and it tells us something fundamental about how re
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Contact: Jade Boyd
jadeboyd@rice.edu
713-348-6778
Rice University
Source:Eurekalert  

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