Revealing a mechanism of antibiotic drug resistance

Scripps Florida research findings could be used to develop a line of antibiotic drugs that are less vulnerable to bacterial mutations

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JUPITER, Fla.—Scientists at the Florida campus of The Scripps Research Institute (TSRI) have made a discovery that illuminates a mystery behind the growing challenge of antibiotic-resistance bacteria. Their research, which identified a mechanism enabling drug resistance, could be used to develop a line of new antibiotic drugs that are less vulnerable to the constant mutation of bacteria. “Understanding this mechanism of resistance allows for the development of new drugs with elements that minimize the emergence of resistance,” Dr. Ben Shen, the TSRI professor who led the study, tells DDNews. “Instead of passively waiting for resistance to emerge and then reacting, we may be able to anticipate potential mechanisms of resistance during a drug’s development.”
The declining effectiveness of antibiotic drugs is widely recognized as one of the major challenges facing modern medicine. The extensive use of antibiotics has enabled infectious organisms to adapt to the drugs that are designed to kill them. The Centers for Disease Control and Prevention estimate that more than two million people suffer from antibiotic-resistant infections each year and at least 23,000 people die due to treatments that are unable to stop infections.
The challenges related to drug resistance have led to a diminishing number of promising antibiotic candidates under development. Shen, whose study was published in Chemistry & Biology, says developing drugs with long-term effectiveness is made more difficult by the lack of knowledge about how drug resistance emerges in bacteria. “Whenever there is a new potential drug candidate, people want to know about the potential for drug resistance,” he says. “Because bacteria replicate so quickly, resistance eventually emerges, but there’s so much we don’t know about how this works.”
TSRI’s study was designed to discover how bacterial resistance works in Streptomyces platensis, a bacteria that protects itself from other bacteria by secreting antibacterial substances. S. platensis belongs to a large family of antibiotic-producing bacteria that accounts for more than two-thirds of naturally occurring, clinically useful antibiotics. “We wanted to know how these bacteria protect themselves, and understand the mechanisms of self-resistance,” says Shen. “It seems possible that this resistance could be spread to other bacteria.”
S. platensis secretes two types of antibiotic compounds: platensimycin and platencin. Shen notes that the recent discovery of these compounds by other scientists represented an important step toward addressing the problem of drug resistance. Both compounds protect against bacteria by interfering with fatty acid synthesis, a process that bacteria rely upon for the production of cell walls. Platencin, although structurally similar to platensimycin, inhibits two separate enzymes in fatty acid synthesis instead of one.
The primary mystery Shen’s team sought to solve was how S. platensis was able to protect itself from the bacteria-killing compounds that it produced. “This bacteria is able to resist its own bacteria, which suggests it creates its own mechanism of resistance,” says Shen. “Ultimately, once this mechanism is understood, it could be used to develop drugs with similar mechanisms of resistance.”
Shen’s team used genetic and bioinformatic techniques to identify two complementary mechanisms in the bacteria that enable S. platensis to resist platensimycin and platencin. They found a pair of genes in the bacteria that make it insensitive to the two compounds through radically simplifying its fatty acid biosynthesis. The researchers used a method that made the bacteria more potent in killing other bacteria, but not the producing bacteria.
TSRI’s research, which was supported by the National Institutes of Health, could provide insight into how other bacteria might use mechanisms such as the one found in S. platensis to bypass fatty acid biosynthesis inhibition. Shen tells DDNews that his team’s discovery could lead to the development of antibiotic drugs that are more effective for longer periods of time. “When a new drug is being developed, researchers could study whether this mechanism is able to destroy that drug. If it does, then the drug is short-lived, and you may be able to make some modifications that improves its resistance,” he says.

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