Indian Mulberry

Drug-resistant microorganisms, major infectious diseases, looming influenza pandemics, and scary biowarfare agents all call out for development of new antimicrobial drugs. While scientists are combing the plant and animal realms for promising candidates, quite a few of their efforts remain hit-and-miss. After many years of testing, the outcomes often disappoint. Meanwhile, even excellent drugs like artemisinin in the treatment of malaria risk losing their effectiveness as poor and ignorant people around the world use them in ways that conduce to the rise of drug resistance.

So there is a palpable need for a source of novel antimicrobials that can keep one step ahead of the rise of drug-resistant bacteria, viruses, fungi, and parasites. Here is one idea for how to obtain them.

A Proactive Approach

Scientists have long worked to identify the secondary metabolites that plants develop to carry out various functions not directly connected with metabolic needs. These functions include defense against microbial invaders, and the metabolites developed have proven a rich source of candidates for drug development for human and veterinarian applications. Thus far scientific researchers have operated in a collecting mode, gathering and sifting through the metabolites that Nature has created. However, it is also possible to shift to a more proactive, experimental mode.

The concept of Metabolite Evolution through Antigen Challenge (MEAC) envisions challenging carefully selected plants with antigens from human pathogens. The aim would be to induce the plants to defend themselves by evolving new metabolites that would specifically counter these challenges. In theory, over the course of several years and in response to repeated challenges, a plant could produce metabolites targeted in ways that would make them highly interesting as drug candidates.

These would include both cytotoxic antimicrobials and secondary products—hormones, ligands, signal transduction molecules, and neurotransmitters—with potential effects on similar human target sites. Additive and synergistic effects might improve outcomes and decrease the chances of drug resistance.

In addition, symbiotic fungi in the plants might evolve their own antimicrobials in response to antigen challenge, and in some case do so more rapidly and in a more effective manner than the plants themselves. So their contributions would need to be collected and evaluated.

Clearly, it would help to select plants with characteristics that would make them perhaps more likely than others to evolve such molecules, including their track records in providing drug candidates and their susceptibility to human pathogens. Also, one would need to consider which plants would prove easiest to cultivate and work with, in some cases in enclosures to ensure that the pathogens do not spread. And planning for long-term use of a plant would require investigation of potential problems in terms of breeding and the relationships of the plants used to wild relatives and food crops.

Likewise, the pathogens would need to be selected with an eye to targeting diseases of special interest, protecting research personnel, and roughly matching the known vulnerabilities of the plants in question, to make it more likely that the plants would indeed be challenged. For example, to seek candidate antimalarials, instead of initially using a potentially dangerous (to humans) plasmodium species, one could test via application to the leaves of a plant or via injection a sample of Toxoplasma gondii, a close but much less dangerous relative of plasmodium. T. gondii typically infects cats. Then, once researchers achieved proof of principle, they could move to careful testing of a plasmodium pathogen that would potentially yield a metabolite targeted against it.

Risks and Rewards

One risk of this research would clearly be that the pathogens would lack virulent action versus the plants.  However, with repeated dosing the pathogens might evolve so as to be able to infect the plants.  A second risk would presumably be that plants (and symbiotic fungi) would not respond rapidly enough to a given human pathogen. As a result, either they would be destroyed by it or, perhaps more likely, they would take so many years—conceivably hundreds or even thousands—to develop effective new metabolites that the cost would become prohibitive long before reaching the goal, or the rapid evolution of microbial drug-resistance would have rendered the original target of much diminished interest. Depending on circumstances, researchers might consider that any project requiring more than 5 or 10 years would not repay the effort. But it is also conceivable that much longer research efforts—25 or even 50 years—could be considered acceptable.

We also don’t know how essential oils in challenged plants might evolve. Since they possess antimicrobial, especially antiviral, properties, the elaboration of new compounds in the essential oils could constitute another beneficial outcome of MEAC, with applications in pharmacology, food preservation, and even perfumes.

Beyond a doubt, MEAC could provide scientists with many findings and insights into how plants respond to new pathogens. Could MEAC also become an unending cornucopia of drugs for treating drug-resistant organisms, TB, HIV co-infections, malaria, emerging infectious diseases, influenza, and biowarfare agents?

There is only one way to find out: experiment.

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Kenneth J. Dillon is an historian who writes on science, medicine, and history.  See the biosketch at About Us.

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