Molecules found to counter antibiotic resistance

Even superbugs have their kryptonite.

Two types of lab-made molecules make drug-resistant bacteria susceptible to antibiotics again, researchers report March 9 in Science Translational Medicine. The discovery could provide new tools in the fight against microbes such as methicillin-resistant Staphylococcus aureus, or MRSA, which causes serious infections.

MRSA and related antibiotic-resistant bacteria can withstand a group of antibiotics called beta-lactams, which includes penicillin and methicillin. “There’s this notion in the pharmaceutical industry that all the low-lying fruits in terms of discovery of antibacterials have been identified,” says Shahriar Mobashery, a biochemist at the University of Notre Dame who was not involved with the study. “So any molecule that has the ability to resurrect beta-lactams, which are proven to be good antibacterials … would be fantastic.”

MRSA is vulnerable to beta-lactams when its ability to make a building block for its durable cell wall is disabled. Scientists at Merck Research Laboratories searched for molecules that interfered with the genes that construct that molecular building block, called wall teichoic acid.

A genetic oddity provided the team with a trick for identifying promising compounds. Blocking genes involved in either an early stage of making teichoic acid or a late stage foils the acid’s production. But hampering only early-stage genes won’t limit bacterial growth, while hindering late-stage genes forces MRSA to stop growing. Strangely, though, the growth-halting effects of blocking a late-stage gene disappear if an early-stage gene is blocked at the same time.   

Hoping to find new targets for rendering MRSA sensitive to beta-lactams, the team searched for molecules that interfered with genes in an early stage of acid-building. After treating MRSA cells with a known late-stage gene blocker to halt the superbug’s growth, the researchers then tested millions of molecules, searching for compounds that reversed this effect and let the microbes grow again. That renewed growth was the calling card the researchers needed to know they’d found an early-stage gene blocker.

Less than 0.2 percent of the 2.8 million molecules the Merck team tested had any effect on bacterial growth. But two compounds successfully blocked the early-stage gene and hindered teichoic acid production. A chemically tweaked version of one of these compounds made over 82 percent of tested MRSA strains vulnerable to a beta-lactam antibiotic. The molecule-antibiotic combination reduced the number of MRSA bacteria in infected mice, and the new compounds appeared to be nontoxic to cells.  

The researchers have filed patents on the new compounds and close chemical relatives, which they expect will be useful in the fight against antibiotic resistance, says study coauthor Terry Roemer, a geneticist at Merck Research Laboratories in Kenilworth, N.J. But the study’s larger significance is conceptual, Roemer says, because it shows the value of targeting genetic relationships to find ways to combat antibiotic resistance. “I hope it inspires others to look more closely at other pathways to see whether a similar sort of genetic phenomenon occurs,” he says.  

Mobashery says the study is exciting because it could provide another weapon for combating serious bacterial infections.  “Whether we are successful in the next 100 years in having effective strategies against pathogenic bacteria … comes down to whether we can have multiple classes of antibacterials,” Mobashery says. “If the answer is yes, you’re going to be successful.”