Virtually all disease-causing bacteria eventually acquire the ability to resist the antibiotic drugs used to treat them. First encountered in hospital patients, antibiotic resistance is spreading at a rapid rate, making some infections more difficult to treat. Recently, scientists supported by the National Institute of General Medical Sciences (NIGMS) have devised creative new strategies to address the problem of antibiotic resistance.
Disarming the Microbes
One solution to the resistance problem is to develop new classes of antibiotics, but these could follow in their predecessors’ footsteps and in time lose their effectiveness. In a different approach, chemists supported by NIGMS have found a way to make bacteria vulnerable to existing antibiotics again.
Bacteria frequently acquire antibiotic resistance by ingesting circular pieces of DNA called plasmids. These plasmids often encode proteins that bacteria can use to thwart the effects of antibiotics. Plasmids are widespread and bacteria readily share them—even with bacteria that cause different diseases. That’s why antibiotic resistance happens so quickly.
The researchers, led by Paul Hergenrother, Ph.D., of the University of Illinois at Urbana-Champaign, have taken advantage of a natural phenomenon called plasmid incompatibility. Incompatible plasmids do not coexist in a bacterial cell because they compete for the same resources and the “stronger” plasmid promptly evicts the “weaker” one. By mimicking this process using a small molecule called apramycin the scientists forced bacteria to expel their resistance-carrying plasmids, effectively re-sensitizing the bacteria to an antibiotic.
Apramycin is probably too toxic to use in people, but Hergenrother is applying the same principle to develop compounds that could be medically useful. Though still in the early stages, this approach holds promise as an effective strategy for combating antibiotic resistance.
Needling Bacteria into Submission
Most antibiotics kill bacteria by fouling up a key biochemical process within bacterial cells. The drugs typically accomplish this by slipping into the bacterial cell and latching onto a key protein, hampering its function. In response, bacteria have come up with myriad ways to evade the drugs’ actions. Many use pumps to rid themselves of antibiotics, while others launch search-and-destroy molecules into their surroundings, wiping out the drugs before they can enter bacterial cells. Still others change the protein that the antibiotic targets so the antibiotic no longer binds to it. The altered protein is still able to carry out its normal function in the bacterium, even in the presence of the antibiotic.
But over time, bacteria have been largely unable to evade a group of molecules called antimicrobial peptides. These molecules are found in a wide range of organisms, including humans, where they serve as a first-line defense against invading germs. Rather than targeting a specific bacterial protein, antimicrobial peptides physically disrupt an entire cellular structure, the cell membrane, much like a needle popping a balloon. The cell membrane helps protect the bacterium from the outside world.
Scientists believe that bacteria are unlikely to develop resistance toward antimicrobial peptides because the cell membrane is a multi-component structure rather than a single biochemical target. In support of this, scientists have observed little bacterial resistance to the peptides. This makes antimicrobial peptides attractive candidates for development into more potent forms suitable for treating infections.
Early attempts to develop antimicrobial peptides into drugs faltered due to several problems. Although the peptides effectively killed bacteria in test tubes, they did not quell infections in laboratory animals unless administered at very high—often close to toxic—doses. The peptides were also difficult and expensive to produce on a large scale.
Now, research supported by NIGMS points to a way around these problems. Scientists led by William DeGrado, Ph.D., of the University of Pennsylvania in Philadelphia chemically synthesized molecules that mimic the activity of the natural peptides. The synthetic molecules can be produced easily and cheaply, and they exhibit potent and broad antibacterial activity in the test tube.
These encouraging results led DeGrado to help found a pharmaceutical company to develop the synthetic molecules into antibiotic drugs. The company is testing compounds that have already been shown to kill over 50 human pathogens. Some of these compounds have high antibacterial activity and low toxicity in laboratory animals. Importantly, bacteria did not develop resistance to three of the compounds in a widely used laboratory test.
If planned clinical trials in humans are successful, the prospect of a significant new weapon in the war on bacterial infection may soon become a welcome reality.
Kirstie Saltsman, NIGMS
Last Updated November 23, 2005
National Institute of General Medical Sciences