It’s a war out there. Even on the level of bacteria and other microbes, there’s a constant arms race, each side developing weapons to target the other’s weakness and defenses against the latest attacks. Humans are key players in this microbial one-upmanship, and so are other organisms. The tools of aggression produced by microbes are applied by higher forms of life and, in some cases, become useful products like human drugs. The vast majority of antibiotics now in use—penicillin, streptomycin, tetracycline, erythromycin, vancomycin, and many others—come from nature.
Yet there is a critical need for effective new medications. The defensive maneuvering that microbes conduct often results in resistance to commonly used antibiotics and other drugs. This resistance has become a major challenge to biomedical scientists.
By teasing apart a three-way scrum found in nature, involving roundworms, bacteria, and insect larvae, researchers in the lab of Jon Clardy, HMS professor of biological chemistry and molecular pharmacology, have discovered a technique for increasing production of antibiotic molecules. Simply feeding the amino acid proline to certain bacteria made them churn out an extra measure of their repertoire of antibiotic compounds. Though it is not certain that any of these will be useful as human drugs, the technique may be valuable in generating lead compounds for testing. The method might also be used with other bacteria to produce a greater variety of compounds with therapeutic potential. The research appears in the Jan. 12 Current Biology.
Natural AlliancePostdoctoral fellow Jason Crawford and graduate student Renee Kontnik, working with Clardy, probed the case of two groups of bacteria, Photorhabdus and Xenorhabdus, that take up residence in the roundworm gut. When these bacteria switch from their resting state to a more aggressive, virulent state, they pump out a mix of molecules that function as antibiotics, digestive enzymes, and insecticidal toxins. These virulence factors enable the roundworms, or nematodes, to kill and consume insect larvae, a nematode staple. The teamwork between nematodes and bacteria is what makes the worms a deadly insect parasite and an effective alternative to chemical insecticides.
But the $64,000 question for biomedical research is: What makes the bacteria switch states? Why do they go from unassuming Dr. Jekylls to virulent Mr. Hydes?
“Because the bacteria are insect pathogens, we thought that some chemical component inside the insect might act as a trigger,” Kontnik said. Indeed, after much experimentation, she and her colleagues found that the transformational signal was proline, a component of hemolymph, the insect equivalent of blood. Apparently, once a nematode infects an insect larva and releases its bacteria by regurgitation, the proline in the insect hemolymph stimulates the bacteria into producing the toxins, enzymes, and antibiotics needed for the team to parasitize the insect. This same switch might be applied to generate new antibiotics for human use—and it might work with other insect-killing bacteria.
“In addition to being a robust source of small molecules with potential biomedical applications, these trilateral symbioses are excellent model systems for understanding host adaptation in bacterial pathogenesis,” Crawford explained.
Energy to BurnAccording to the investigation, proline maintains an energy-storing mechanism of the bacteria called the proton motive force, or PMF. Adding more proline boosts the level of stored energy, signaling to the bacteria that it’s time to expend energy by producing more antibiotics and other compounds that equip them for aggressive behavior. When the researchers manipulated the PMF directly, they saw a similar spike in antibiotics and other virulence factors.
“It is likely that these bacteria use PMF to control other mechanisms of virulence–pathogenesis as well,” Kontnik said, “and this idea might be applicable to controlling human pathogens.” If manipulating the PMF one way in the lab causes the bacteria to turn on antibiotics and other virulence factors, opposite manipulation of the PMF in a bacterium infecting the human body might turn off bacterial virulence, controlling infection.
“The next steps,” Clardy said, “are sorting out the antibiotics that are being made to see what lessons they might hold. In the longer run, we’ll explore the generality of using these types of symbiotic systems to understand how bacteria make decisions in addition to potentially useful small molecules.”
Students may contact Jon Clardy at jon_clardy@hms.harvard.edu for more information.
Conflict Disclosure: The authors declare no conflicts of interest
Funding Sources: The National Institutes of Health and a Damon Runyon Cancer Research Foundation fellowship for Jason Crawford; the authors are solely responsible for the content of this work.
