Antibiotic-resistant infections are a global public health emergency. Researchers are looking to insects as possible sources of new therapies.
What began as an informative trip to an exotic theme park filled with dinosaurs quickly turned into a nightmare for many characters in the 1993 film, Jurassic Park. The movie centers on extracting dinosaur DNA isolated from amber-preserved mosquitos that had fed on these extinct giants. In short, the DNA was used to clone dinosaurs, which eventually caused havoc once they escaped. The premise made for an entertaining film, but might there be some element in this story that could benefit human health, and not just entertain?
In today’s healthcare landscape, we face a major public health emergency across the globe—antibiotic-resistant infections. This risk is so compelling that, on September 21, 2016, The United Nations General Assembly (UNGA) adopted a Political Declaration to combat the global threat of antimicrobial resistance, making it the fourth health topic since the inception of the UNGA in 1946 to receive such attention (the other three being HIV, Ebola, and non-communicable diseases). Unlike Jurassic Park’s mad-scientist investor, John Hammond, who wanted to create a Disneyland of dinosaurs, modern scientists are looking at insects as possible sources of new therapies to treat life-threatening infections. It makes sense in many ways, and the clues are certainly theremany insects are social (eg, ant colonies). If one of them were to get infected, they could bring that infection back to the colony and completely wipe it out. Over millions of years these creatures have developed tools to combat this risk, one of which is the “innate” immune response, fueled by antimicrobial peptides. Peptide therapeutics capture the Jurassic Park theme. The specific carryover from Jurassic Park is related to where possible new treatments can be sourced for human therapies; the answer? Insects. Insects live a very short lifespan compared with humans (on average, approximately 30 days); they are an incredibly successful species on the planet, having been present for more than 200 million years continuously and represent far more biodiversity than plants and animals put together. There are an estimated 5.5 million insect species on Earth, with only 20% having been characterized. Ross Piper, an entomologist at the University of Leeds, calls the focus on insects in medical research “ecology-led drug discovery”. Insects are constantly in contact with environmental pathogens and have evolved a different set of defenses from humans. Unlike humans, insects lack an “adaptive” immune response and rely on their “innate” or “rapid” immune response that has evolved distinct tools to foster their success on the planet (Figure).
In general, one of these tools, antimicrobial peptides, have been engineered through natural selection to attack bacteria and activate the immune system quickly, which makes sense for an organism that only lives for 30 days. Innate immunity is 100 times more energy-efficient than adaptive immunity, with far less DNA required for the requisite protein machinery. This economy from natural selection has resulted in a defense mechanism that results in rapid reaction time to infection–such peptides can be found in insects 2 to 4 hours after a bacterial challenge, well over 100 times faster than antibodies would be generated in humans.
The availability of these peptides permits scientists to adapt them for human use and identify potentially novel targets in bacteria. One such novel target is protein folding. For bacteria to carry out normal functions, they require the tools, typically in the form of proteins. These proteins need to be built correctly, which in general means that there shouldn’t be any errors from DNA to protein coding and that these proteins are folded in the right way to make sure they will function appropriately. A subgroup of insect-derived peptides has been found to inhibit this folding function; without properly folded proteins, a bacterium can’t do what it is supposed to do, making it more susceptible to various stressors. Use of these “folding inhibitors” can kill bacteria directly, as well as improve the use of older antibiotics that may currently seem ineffective.
The lessons learned from natural selection will hopefully save many lives and serve as a foundation to develop long-lasting treatments against the growing challenges of antibiotic resistance at the bedside.