(Credit: Yusnizam Yusof/Shutterstock) Somewhat like looking down the barrel of a gun, antibiotic resistance is a looming threat to modern medicine. The rise of MRSA, super drug-resistant gonorrhea and other “nightmare” bacteria risk rendering our microscopic defenses useless. What to do when your last-last-last resort fails to kill these pathogens? Someday, perhaps sooner than later, we’re going to need new antibiotics, not to mention medicines for cancer, depression, and other conditions that aren’t readily treatable by current prescriptions. So, how do we find new pharmaceuticals? Some argue that we’ve reached “peak pharma,” but Ross Piper, an entomologist and research fellow at the University of Leeds, contends that we haven’t even begun looking. Our best bet may be beneath our feet, in the diminutive world of insects, and he says this research might also ignite conservation efforts. “It could be a treasure trove of useful chemistry. Look at what compounds have been isolated from reptiles and snakes,” Piper said in a video call with Discover. His favorite example is exenatide, a synthetic hormone that treats diabetes mellitus type 2, originally derived from the saliva of Gila monsters. Between 2014 and 2016, sales of this drug reached $2.49 billion. “Who would have thought just by looking at the compounds in the saliva of a bloody lizard that you can produce a blockbuster drug for type 2 diabetes?” For the past year, Piper has been engaged in what he calls “ecology-led drug discovery,” and he believes insects are the most promising lead. Bugs and other arthropods, awash in a tiny world of filth, need to protect themselves from disease, and have evolved many novel defenses. While insect bioprospecting, as it’s called, is not entirely new, there’s much to be done. There’s an estimated 5.5. million different insect species on earth, but only around 20 percent have been described. Yet, entomologists are becoming scarce—so why isn’t bioprospecting bugs more popular? Millions Of Insects, Millions Of Chemical Defenses Humans have known about the medicinal benefits of compounds derived from insects—anti-bacterials, analgesics, anticoagulants, diuretics and antirheumatics—for hundreds, if not thousands, of years. In a 2005 review, Eraldo Costa-Neto identified 64 different arthropod species from around 14 orders, all used medicinally by different cultures across five continents. In traditional Korean medicine alone, there are at least 19 insects and other arthropods commonly prescribed, including centipedes, cicada nymphal skins, and ghost moth larvae infected with the paralyzing fungusOphiocordyceps sinensis. More recently, scientists found that wasp venom can pop cancer cells while alloferon, a peptide isolated from the blood (hemolymph) of a species of blow fly, has antiviral and antitumor properties. But one of the biggest problems is scaling. Once you find a chemical in something as tiny as a fly, how do you make sure you can make enough of it? “Previously, you would have been restricted by not being able to find sufficient quantity of that particular species,” Piper says. “You maybe needed thousands of them to be able to extract enough of whatever that produces from whatever gland you're looking at. But you can do that with much smaller quantities now.” With advances in transcriptomics, not to mention all the buzz about CRISPR-Cas9, Piper believes we can isolate certain genes and insert them into the cell line of something else to mass-produce it. Alternatively, you could insert genetic material into other insects, such as crickets or mealworms, and mass-produce medicine this way. “You could put vaccine genes or something like that, like they do in tobacco, into insects,” explains Aaron Dossey, an entomologist and pioneer in the insect-based food industry. He's also the founder of All Things Bugs, a company that manufactures whole cricket powder. “Then use them as a mass production vehicle for your vaccine, your possible drug of choice or enzyme or bioactive peptide or some vitamin.” Dossey suggests that stick insects or phasmids make “attractive model organisms for biosynthesis studies” due their large size and wide range of chemical defenses. “Given the number of phasmid species analyzed…the number of novel compounds found in phasmids so far, and the total number of species in this order, phasmids represent a significant potential source of new compounds,” he wrote in a 2010 analysis. Putting The Ant In Antibiotic Among the most promising bugs to look for drugs are eusocial insects, especially in the order Hymenoptera — bees, wasps and ants. An anthill, which can contain hundreds of millions of workers with high genetic relatedness in compact, clustered living quarters, is the perfect place for disease outbreak. “If one individual gets infected, a worker could spread it to thousands of individuals within a few hours,” says Clint Penick, an assistant research professor at Arizona State University who studies ant relationships. “Soil is the most by microbially dense and diverse habitat on the planet.” Therefore, ants need strong antimicrobials, which many species secrete from the metapleural glands on their back. In research published inRoyal Society Open Science in February, Penick and his colleagues tested the antimicrobial strength of 20 different ant species against Staphylococcus epidermidis, a common, generally benign, skin-dwelling bacteria. Using a vacuum-like device called a pooter, he collected ants from the sidewalk, in his backyard and on the way to work at North Carolina State University, where he was researching at the time. “We hit all three of the major ant sub-families, which is a pretty good breadth of their diversity,” Penick says. Sixty percent of the ants tested inhibited bacterial growth, but efficacy was not dependent on colony population or even the size of the ant. In fact, one of the smallest ants tested—the thief ant, Solenopsis molesta—displayed the strongest antimicrobial properties. The exact chemical properties behind these insects’ homegrown pharmacopeia is unknown. More research is needed to isolate these substances, but it’s getting easier all the time. “What we developed was a method where you can measure a lot of ant species at once. We were able to run 96 samples in a day whereas other groups might be able to just run a couple dozen,” Penick says. “We've shown that we can scale this and look at more species. We've also narrowed down a little bit about which species might be interesting.” No Rock Left Unturned It’s easy to overlook some compounds because lab-grown insects often rely on native plants in their diet in order produce the same chemicals. For example, blister beetles, especially the so-called Spanish Fly, are noted for the extremely toxic cantharidin they produce. A terpene commonly used in wart cream, cantharidin has some anti-tumor properties, and can even potentially treat cardiac failure. Male meloid beetles gift cantharidin to females, who in turn squirt it on their eggs to deter predators. They can make it themselves, but other so-called canthariphilous flies have to accumulate this blistering chemical by chomping on bastard teak, Butea frondosa, flowers or eating bugs that produce it. Rove beetles also produce a vesicating toxin with potential antitumor properties called pederin, which they make using endosymbiotic bacteria that live in their hemolymph. Likewise, brown planthoppers make antibiotics using symbiotic bacteria. So try to study these insects without the right diet or habitat and you may not find the same interesting chemicals, according to a 2010 analysis by Konrad Dettner, a now retired entomologist from the University of Bayreuth who specializes in the chemical ecology of insects. “[W]hen bacteria or fungi were isolated from the insect hosts…in most cases these compounds have not even been shown to be present within the insect hosts,” he wrote. “Therefore, the biological significance of these natural compounds in symbiotic or parasitic systems where insects represent hosts is usually not known.” This is partially why Piper argues that this type of research can benefit conservation efforts. Not only is preserving original habitats important for understanding chemical relationships, for every forest or swamp that is bulldozed into a Starbucks, there’s potentially billions of dollars worth of medications being destroyed. However, in his exenatide example, not a single cent of the billions generated from this hormone has gone back to preserve the home of the lizard where it was discovered. “If you did find something and it was really successful, you could completely revolutionize the amount of cash available for conservation work,” Piper says. “We’re losing species that could have all sorts of potential applications. But then…you have to tread a fine line, because you can easily go down the road of putting a monetary value on things.” Insects, it turns out, may be priceless.