New theory explains antibiotic mechanism

By: Sam Ohmer

Posted: 12/4/08

Antibiotics are likely the most widely used medicines in the world. Early antibiotics were already in use in ancient Egypt and Greece, and it has been over a century since it was discovered that antibiotics kill bacteria.

But remarkably, the precise mechanism by which antibiotics work is still unknown. A research group at Boston University has taken a step toward supporting a new theory of antibiotic activity.

The theory holds that antibiotics introduce free radicals into bacteria. Free radicals are highly energetic particles that can be produced by and result in damage to cells. Scientists are working to determine what role free radicals might play in the functioning of antibiotics.

The Boston University and Howard Hughes Medical Institute group have observed that antibiotics are indeed able to trigger the production of free radicals in bacteria.

"We were interested in understanding more about the pathways and systems that antibiotics utilize, which are involved in cell death following treatment with antibiotics," head of the Boston group Michael Kohanksi said.

"We had shown last year that bactericidal antibiotics, those drugs which kill bacteria, can use a common radical-based pathway which contributes to the killing seen with these drugs. At that point, it was still unclear how different antibiotics with completely different targets can induce a common killing pathway," Kohanski said.

Kohanski's group is concerned with a central question in the study of antibiotics. There are several different classes of antibiotic compounds, each with its own structure, method of delivery into the cell and targets within the cell.

But these diverse drugs all lead to the same endpoint: cell death. Unlocking this conundrum might open the door to newer and better antibiotic compounds. The key seems to be small organelles in bacteria called ribosomes, according to Kohanski's research.

Ribosomes are the site of protein synthesis in all cells. Under normal conditions, ribosomes take in messenger RNA (mRNA), a molecule that basically acts as a mirror copy of the DNA sequence. Ribosomes are able to match up the mRNA sequence to peptides, the single-unit building blocks of proteins, thus creating a specific chain of peptides.

Antibiotics work to disrupt this usually effective process. If the mRNA sequence is a group of excited children waiting for their presents on Christmas, and the presents were the peptides, then antibiotics would be the Scrooge who went around switching all the name tags on the presents so that child A would get child G's present, and child U would get child C's present, and so on and so forth.

If the mRNA sequence isn't being matched up with the right peptide sequence, then the proteins that are being pumped out are going to be pretty odd.

This manipulation of the ribosomal machinery leads to the production of faulty proteins. When a cell's proteins do not work properly, this introduces stress into the cell - often via the creation of free radicals. Free radicals are atoms with an unstable unpaired electron that react quickly to steal another atom's electron to satisfy themselves.

When free radicals steal other atoms' electrons, however, this creates free radicals that then go on to steal other electrons, and so on. These radical chain reactions, as they are known, can propagate damage throughout the cell.

When too much oxidative stress is built up from free radicals floating around in the cell, the cell will die. Thus, the antibiotic has conquered the bacteria, and the organism playing host to this epic battle avoids a bacterial infection.

This enhanced understanding of how antibiotics work could prove invaluable, especially since the problem of bacterial resistance to antibiotics is looming larger and larger all the time. Kohanski realizes the importance of this looming problem.

"Our work has uncovered new pathways that could aid in the design of combination therapies for [antibiotics]. A compound targeting the pathway we have uncovered could be used in combination with an [antibiotic] to enhance the potency of this drug class. This means that we could use less antibiotic which would reduce drug side effects while still maintaining the ability to fight an infection."