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Scientists have long wondered why bacteria contain so many "redundant" enzymes. Why do multiple molecules that do the same job interchangeably, while it would be much more efficient to make one than one?
A new study from the University of Washington at St. Louis suggests that many of these so-called redundant enzymes are in fact specialists that ensure maximum growth in different environments.
In addition, it was found that these specialized enzymes increased E. coliAntibiotic resistance to antibiotics in low pH conditions, such as those found in the gastrointestinal tract or the urinary tract – raises concerns that current antibiotic susceptibility testing is inadequate. Petra Levin's laboratory research, a professor of biology in the arts and sciences, is published April 9 in the journal eLife.
"Certain enzymes that appear redundant for bacterial growth and fitness under standard laboratory conditions are specialized for particular environmental conditions," said Elizabeth Mueller, doctoral candidate and first author of the new study. "We are probably missing a lot of interesting and clinically relevant biology by studying bacterial cells predominantly during growth in an aerated growth medium at neutral pH and neutral nutrients."
Mueller discovered that a subset of enzymes involved in manufacturing E. coli Cell walls are pH specialists that guarantee robust growth and cell wall integrity over a wide pH range. The work was carried out with collaborators from the University of Newcastle in Great Britain and the University of Utrecht in the Netherlands.
Why so much?
It's like opening someone's closet, finding a bunch of shoes and asking, "Why so much?" If a person can get along with just one pair – and whatever – why keep all the others? On closer inspection, however, you will find that this pile of shoes is made up of sneakers and hiking shoes, woolen slippers and rain boots, flip-flops and stiletto heels. These are all shoes, but different styles are suitable for different occasions. You could wear a pair of rubber boots on a three kilometer run, but you would have fewer blisters in your sneakers. The same thing seems to be true for E. coli Cell wall enzymes under different pH conditions.
For this study, the authors generated E. coli which lacked non-essential enzymes of the cell wall. These strains were then cultured in a medium with a pH representative of what E. coli would find in the lower gastrointestinal tract and urinary tract. The authors found that under these conditions, instead of being interchangeable, several of these enzymes helped the E. coli grow better.
The study is focused on two specialized enzymes in pH: PBP1a and PBP1b. PBP1a was required for maximal growth under alkaline conditions, while PBP1b was required under acidic conditions. If a cell lacks one of these enzymes and is grown in the "specialist" pH condition of that enzyme, its viability will be reduced.
Interestingly, the redundancy in cell wall synthesis seems to have consequences for E. coliSensitivity of some active antibiotics on the cell wall. The activity of PBP1b under acidic conditions increases the resistance of the cell to specific beta-lactam antibiotics up to 64 times greater than that of growth under standard culture conditions.
"Most clinical laboratories test antimicrobial susceptibility by growing bacterial cultures in a nutrient-rich environment at near-neutral pH," Mueller said. "These conditions poorly reflect those of pathogens in most sites of the human body."
"Our study supports the idea that environmental conditions at the site of infection can affect the effectiveness of antibiotic treatment," she added.
Future work on the mechanism of protection of the cell by PBP1b could reveal new antimicrobial targets that can be inhibited under pH conditions. In addition, Levin laboratory researchers predict that future research will identify similar specialists of enzymes in other bacteria. These specialists could explain the high levels of redundancy in other clbades of enzymes, especially those located outside the cell and exposed to the environment.
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This research was funded by the National Science Foundation (DGE-1745038), Wellcome (101824 / Z / 13 / Z) and the National Institutes of Health (NIH) (MIRA, GM127331 and GM64671).
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