To Control Germs, Scientists Deploy Tiny Agents Provocateurs

Reporting the work here on March 13 at the 229th national meeting of the American Chemical Society, chemistry professor Helen Blackwell described the ongoing construction of a new class of molecules that conduct such chemical warfare.

Targeting natural signaling mechanisms in bacterial cells, Blackwell aims to ultimately control the formation of biofilms, goo-like amalgamations of bacteria that are widespread in nature and have serious implications for agriculture and human health. Biofilms form the green slime on rocks, the plaque on human teeth and the slippery film on ship hulls. If a single cell were analogous to one man, biofilms would be the "bacterial equivalent of mob mentality," says Blackwell.

In the realm of health, biofilms are at the root of growing numbers of tenacious, and sometimes fatal, hospital infections, says Blackwell. Indeed, a U.S. National Institutes of Health study last year reported that almost 80 percent of bacterial infections are in the biofilm forma.

Biofilms can often constitute several species of bacteria and can be both harmful and beneficial. In one role, biofilms can coat plant roots and symbiotically aid ecological processes such as nitrogen fixation. But at the darker end of the scale, biofilms can form infection-inducing layers on implanted medical devices and cause deadly lung infections in cystic fibrosis patients. Biofilms have long baffled researchers because of their stupefying capacity to behave like a "super-organism" that vetoes the normal characteristics of a bacterial cell in favor of new group behaviors. "It's amazing that such simple organisms as bacteria can form these super-colonies that work together in such sophisticated ways," says Blackwell.

Scientists have learned that bacteria sense each other and the overall density of their colony by continuously exchanging small molecules and peptides - a process known as quorum sensing. Past a certain density threshold, the colonies unite to initiate group behaviors, such as biofilm formation.

Attempting to manipulate quorum sensing in both plant and animal bacteria, Blackwell and her team are designing new compounds that mimic acylated homoserine lactones (AHLs), a natural molecule that is used by more than 50 species of bacteria to "talk." Researchers have so far studied around 15 variations of AHLs. In particular, the UW chemists are synthesizing molecules that interact with a specific class of proteins that are linked to AHLs and are critical in quorum sensing.

"We want to design molecules to confuse bacteria so they can't sense their neighbors," says Blackwell, "but some types of quorum sensing are beneficial, so we are simultaneously searching for compounds that selectively turn on group behaviors."

Using new combinatorial chemistry techniques, Blackwell and her team are screening through hundreds of molecules at a time. The researchers have so far unveiled three promising organic compounds that seemingly quell bacterial signaling.