In general, new antibiotics are needed to address the problem of increasing antibiotic resistance. Infections with Gram negative bacteria are particularly challenging to treat. The cellular structure of Gram negative bacteria prevents penetration by many antibiotics and renders many Gram negative pathogens intrinsically antibiotic resistant (Zgurskaya, H. I., Löpez, C. A., & Gnanakaran, S. 2015.) Previously, very few antibiotics have been identified that specifically target Gram negative bacteria. Polymyxin is one example, which functions by disrupting the cell membranes of Gram negative bacteria, destroying their ability to function as osmotic barriers. Rising antibiotic resistance in Gram negative bacteria has threatened the available antibiotics and has highlighted the urgency to discover new antibiotics that specifically target Gram negative pathogens. Therefore, the discovery of Darobactin was of high interest in the medical and biotechnology fields due to the potential implications for the treatment of life threatening infections with Gram negative pathogens.
The Antimicrobial Discovery Center at Northeastern University, led by Biology professor Dr. Kim Lewis, published their findings on Darobactin in 2019 after two years of research. Darobactin was found in the bacteria Photorhabdus, by Yu Imai, a Northeastern University research associate. The bacteria Photorhabdus was found in the gut of a parasitic worm that is found in soil called a nematode. In the microbiome of the nematode gut, Photorhabdus releases toxins that kill the worm’s prey which allows the worm to digest it.(Candanosa, 2019) Darobactin was discovered in a screen of Photorhabdus isolates to identify compounds produced at a low level that may be encoded within a “silent” biosynthetic gene cluster. This screen identified Photorhabdus khanii HGB1456, and the secreted compound, Darobactin, was found to inhibit the growth of Gram negative bacteria, but not Gram positive bacteria. This drug was tested to treat infections from gram negative infections such as E.coli and Klebsiella. They were able to kill these infections without being toxic to the body, as demonstrated in a mouse infection model. (Imai et. al. 2019)
Darobactin, with a chemical formula of C47H55N11O12, is present in the L configuration with two chiral centers and has an unusual structure that has two fused rings that form post-translationally. It is coded by a silent operon and synthesized by the ribosome. Horizontal gene transmission is used to code for Darobactin. The bacteria gathers DNA from the environment and incorporates it into the genome. A unique feature of this antibiotic is the fact that there is a tryptophan-lysine bond between two un-activated carbons. The Darobactin molecule is quite large with a size of 965 Da which is comparable to polymyxin. (Imai et. al. 2019)
Mode of action
Describe what is known about the mechanism of action of the antibiotic.
Summarize key points and future research.
[Sample reference] Takai, K., Sugai, A., Itoh, T., and Horikoshi, K. "Palaeococcus ferrophilus gen. nov., sp. nov., a barophilic, hyperthermophilic archaeon from a deep-sea hydrothermal vent chimney". International Journal of Systematic and Evolutionary Microbiology. 2000. Volume 50. p. 489-500.