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Pair of studies offer new clues to combat antibiotic resistance

January 25, 2006

In the continuing battle against antibiotic resistance, two new studies shed light on the complex defense mechanisms pathogenic bacteria use to evade antibiotic attack, an understanding of which could lead to new, more effective antibiotics to help save lives and combat the growing problem of antibiotic resistance. The studies, both of which target chemical components in the protective membrane surrounding bacterial cells, will appear in the February 17 inaugural print issue of ACS Chemical Biology, a new monthly publication of the American Chemical Society, the world's largest scientific society.

In one study, researchers from the University of Michigan College of Pharmacy in Ann Arbor and the Borstel Research Center in Germany genetically engineered a strain of E. coli so that it lacks its normal outer protective layer of lipopolysaccharides, complex structures that help them defend against antibiotic attack. Removal of this layer is believed to make E. coli and other gram-negative bacteria more vulnerable to antibiotic attack, the scientists say.

"The study is further proof-of-principle that the spectrum of activity of antibiotics can be significantly extended by targeting the formation of lipopolysaccharides in the outer membrane," says study co-author Timothy C. Meredith, Ph.D., a medicinal chemist who conducted the research as a doctoral student at the University of Michigan with Ron Woodard, Ph.D., a professor of medicinal chemistry at the university. Meredith is currently a researcher at Harvard Medical School in Boston.

Gram-negative bacteria, considered among the most virulent, include strains that are known to cause food borne illness, bubonic plague, Legionnaires' disease and cholera, among others. They are among the most difficult bugs to control using antibiotics, researchers say.

In another study published in the journal, researchers at Harvard Medical School and Harvard University built synthetic versions of natural substrates used by key enzymes to make teichoic acids, polymeric structures in the membrane surrounding gram-positive bacteria. The polymers are considered essential for bacterial survival. Until now, these enzyme precursors have been difficult to study due to their presence in low amounts, complexity and insolubility, says study leader Suzanne Walker, Ph.D., a professor in the Microbiology Department at Harvard Medical School.

The availability of synthetic precursors will make it easier to study how the gram-positive bacterial membrane is formed and aid in the design of new antibiotics to block its formation, says Walker. Her lab will soon begin screening for compounds that can block this important chemical pathway, she says.

Gram-positive bacteria include anthrax and other strains that cause upper respiratory infections and sepsis. In comparison to gram-negative bacteria, they are generally considered easier to control with antibiotics.

"Antibiotic resistance is a huge problem that is only going to get worse. We need new targets, especially if we're going to circumvent resistance," Walker says.

Both research teams caution that these new approaches may be years away from human testing and clinical use. Even if effective, bacteria can eventually develop ways to circumvent even the best laid approaches, underscoring the need for a better understanding of resistance machinery and the availability of new antibiotics, they say. Limited and selective use of antibiotics to prevent their overuse is also a way to stem resistance, according to health experts.

American Chemical Society