Web Date: June 27, 2014
Natural Product Ferries Antibiotic Into Bacteria
Chemists struggle to develop antibiotics for gram-negative bacteria such as Escherichia coli because, in part, the microbes have a second cell membrane outside their cell walls that can deflect drug molecules. Now researchers report that they have successfully linked β-lactam antibiotics to a natural product produced by many bacteria, allowing the drug to slip into and selectively kill E. coli. (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja503911p).
To shuttle microbe-killing compounds across bacterial cell barriers, researchers have long looked to catch a ride with molecules made by bacteria that can pass by these defenses. Iron-scavenging compounds called siderophores have been a popular choice because bacteria synthesize them to collect scarce metal ions in the environment and bring them back to cells. Though many researchers have tried to use siderophores to carry cargo into bacteria, they’ve had limited success, says Elizabeth M. Nolan of Massachusetts Institute of Technology.
In 2012, Nolan and her team showed that they could ferry nontoxic molecules into bacteria using a well-studied natural siderophore, enterobactin (J. Am. Chem. Soc., DOI: 10.1021/ja3077268). They attributed their success to how they attached the cargo to the siderophore: They added a linker molecule at a location that would not perturb enterobactin’s ability to bind to iron or to its target receptor.
In this new study, Nolan and graduate student Tengfei Zheng synthesized structures that linked enterobactin to two different β-lactam antibiotics, ampicillin and amoxicillin. They then looked at the activity of the new antibiotics against various strains of E. coli under low iron conditions. All of the strains were more susceptible to the antibiotic-siderophore conjugates than to the unlinked drugs. For one strain that infects the urinary tract, called CFT073, the new compounds were 1,000 times more potent than the unlinked ones. In further experiments, Zheng and Nolan showed that FepA, a protein in the bacterial outer membrane that transports siderophores, is essential for the activity of these linked antibiotics.
Other groups trying this strategy have focused on siderophores that bind tightly to iron, says Marvin J. Miller of the University of Notre Dame, but this study demonstrates the importance of not disturbing the molecular recognition between siderophores and their receptors.
Nolan and Zheng also found that these conjugates were not potently active against a broad spectrum of bacteria. For example, in co-cultures of E. coli CFT073 and gram-positive Staphylococcus aureus, the S. aureus colonies survived treatment with low concentrations—1 µM—of the linked antibiotic, but the E. coli colonies didn’t. This species-specific killing could eventually be a useful tool for clinicians, Nolan says. For an infection with a known cause, doctors could choose an antibiotic that kills the pathogenic bacteria while leaving beneficial ones to thrive.
This potential for bacteria-selective antibiotics is “exciting,” Miller adds. “This approach could help us keep one step ahead in the never-ending microbial war.”
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