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June 13, 2017
Retooling an old antibiotic
At a Glance
- In the lab, novel compounds thwarted bacteria that are resistant to the antibiotic vancomycin.
- The findings may lead to the development of drugs to treat antibiotic-resistant infections.
Antibiotics may cripple bacterial growth and replication in many different ways. Some prevent bacteria from growing new cell walls. Others cause cell walls to weaken and burst. Another mode of action is to interfere with bacterial DNA or proteins.
Over time, antibiotics can stop working because bacteria develop resistance. Some bacteria have become resistant to multiple antibiotics. Treating infections by these microbes can be tricky or even impossible. To combat this public health threat, scientists have been working to develop novel compounds that are effective against antibiotic-resistant bacteria.
A team led by Dr. Dale Boger of the Scripps Research Institute designed and synthesized a series of compounds based on the structure of the antibiotic vancomycin. The study was supported by NIH’s National Cancer Institute (NCI) and National Institute of General Medical Sciences (NIGMS). Results were published in the Proceedings of the National Academy of Sciences on May 30, 2017.
The researchers exploited their knowledge of how antibiotics work to modify three functional parts of the vancomycin molecule to design novel structures. They tested the compounds in several ways. The most effective, compound 18, was 10,000 times more potent than vancomycin at inhibiting the growth of vancomycin-resistant bacteria. The scientists demonstrated that compound 18 had three independent and synergistic modes of action.
The researchers also measured the development of antibiotic resistance to the compounds. As time passes, bacteria can develop resistance to an antibiotic. After resistance develops, it can take a much larger dose of antibiotic to inhibit bacterial growth. Every day for 50 days, the team exposed vancomycin-resistant bacteria to each compound. Even after 50 days, compound 18 continued to inhibit growth with only a four-fold increase in the relatively small dose needed. For the other compounds, far more (between 8-fold and 128-fold) was needed to control growth by the 50th day.
For an antibiotic to be safe, it has to kill bacteria without harming human cells. When the researchers assessed the toxicity of the new compounds, none was toxic to red blood cells, mammalian cells, or a human cell line.
Boger explains that having three independent modes of action improves the likelihood that an antibiotic like compound 18 will be effective for a long time before bacteria can develop resistance. “Doctors could use this modified form of vancomycin without fear of resistance emerging,” Boger says.
These findings one day could lead to the development of a new antibiotic. However, testing for safety and effectiveness in people is still needed.
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References: Peripheral modifications of [Ψ[CH2NH]Tpg4]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics. Okano A, Isley NA, Boger DL. Proc Natl Acad Sci U S A. 2017 May 30. pii: 201704125. doi: 10.1073/pnas.1704125114. [Epub ahead of print]. PMID: 28559345.
Funding: NIH’s National Cancer Institute (NCI) and National Institute of General Medical Sciences (NIGMS).