Plant-Derived Antifungal Agents: Challenges at the Level of Clinical Trials

A large number of plant products have been studied for their antimicrobial potential against various infectious diseases, but the fungal disease Candidiasis has received much less consideration. The disease Candidiasis is characterized by the multiplication and dissemination of pathogenic fungal species of Candida. Many plant-based herbal treatments formulations were found to have important antifungal activity and have been extensively fractionated to understand antifungal potential. Such formulations were further confirmed in animal models; however, they did not come up at the level of clinical trials. Because such herbal formulations possess good potency to have a significant anticandidal activity without producing remarkable toxicity or side effects. ¹

Candidiasis is largely associated with the infection of bacteria Candida species and is known to be one of the principal causes of mortality and morbidity in immunocompromised patients. This disease is related to poor immunity in the person, which includes a high incidence of illness among those people. Azole, amphotericin are recommended antifungal medicines; however, they are showing resistance in most parts of the globe. Over the last few years, antifungal resistance has been reported in clinical strains of Candida. Antifungal resistance is a worldwide problem growing continuously, and only a few chemical drugs are available to the market, so there is a vital need for new antifungal drugs to treat resistant fungal infections. ² According to the World Health Organization (WHO), drug resistance is becoming an emergency for public health with unknown proportions because every year it is responsible for numerous deaths, and the social costs of healthcare have been estimated in billions. Meanwhile, new forms of antifungal resistance have also been reported, and clinicians have an insufficient weapon to encounter fungal infections. Despite the recognised need for effective antifungals, the reality is that only one or two antifungal classes have been brought to the market in the past few decades. ³ At the forefront of research, there is a crucial necessity for a larger understanding of how human fungal pathogens develop resistance to them, how antifungals work, and what molecular mechanisms could be exploited to circumvent fungal defence mechanisms. Therefore, switching over to the use of herbal compounds of medicinal importance is an important step to control candidiasis because the importance of herbs was recognized as traditional medicine for Indian civilizations, China, and other countries. As we know, the globe is a rich source of herbs having antimicrobial properties. On the basis of these backgrounds and importance, we would like to explore herbs that would be a safe and cost-effective therapy for countering Candidiasis. Escalating antifungal discovery from diverse natural compounds has an enormous capacity to produce various secondary metabolites with prudent antifungal activities. ⁴ Indeed, significant research is needed to unlock new avenues for natural products discovery; however, most of the natural products do not reach the level of clinical trials. The article is focused on discussing what are the problems, hurdles, and challenges to enter into the clinical trial with natural antifungal agents that is studied in vitro and in vivo.

Problems Associated with Clinical Trials and Manufacturing of Natural Antifungal Drugs

Searching for novel herbal sources as potent antifungal drugs is urgently needed to develop safe antifungal. Natural resources have made an invaluable contribution to the process of drug discovery and development over the last few decades. Herbs are the most important source of bioactive natural compounds; however, natural molecules with potential antifungal therapeutic applications are still in the row and to be discovered from the various plant sources. ⁵ Natural resource is poorly explored and studied, and promises could be raised in the prospect of discovering novel compounds with potential antifungal. ⁶ In this context, bioactive compound isolation programs are reoriented toward future study on largely unexplored plants. They should be characterized by biochemical assay and biophysical analysis conditions. On the basis of these studies, a series of bioactive molecules can be identified as a potential drug for diarrhea. ⁷ In continued efforts to discover novel natural molecules, unexplored plant sources should be characterized. The drug discovery process includes initial target identification, target validation, high-throughput molecule screening, hit/lead identification, assay development, lead optimization, and finally the selection of a candidate molecule for clinical study. ⁸ Researchers have isolated, characterized, and reported potent antifungal compounds from time to time from natural sources, and they should undergo clinical study; however, they are not pursued or followed up strongly for clinical studies. This is a major drawback due to which a potent compound fails to come to market in the form of drugs. Most of such kind of research is left at the bench due to a lack of funds, proper interest, and participation in clinical trials. This is the reason only a few clinical trials of natural compounds are available on clinicaltrials.gov. ⁹ This article discusses why natural antifungal products did not come to clinical trial level pointwise (1) Preclinical results of a natural compound usually do not translate to clinical trials. In vitro preclinical experiments often involve continuous high-concentration exposure to a natural product of interest. This type of exposure is typically not possible in humans, and it needs to be optimised. (2) Oral medications of natural products might have limited bioavailability. Therefore, researchers have to work on improving the bioavailability of natural products. (3) As we know that a natural product cannot be patented. Therefore, do not have the control of pricing or the power of pricing that would allow them to pay the cost of clinical trials. A clear and effective policy is needed to regulate it. (4) Preclinical efficacy does not necessarily translate in humans because, many times, clinical trials of natural products have produced conflicting results. (5) Starting clinical trials on a new natural product is problematic due to some regulatory requirements. A large number of patients suffering from fungal infection are required to start the trial. To establish the efficacy of a compound, a lot of patients are needed for each clinical indication. Enough no. of patients with the resistant fungal strain should be included for investigation to demonstrate that the natural antifungal agent is not inferior as compared to approved antifungal drugs. (6) The costs of carrying out a clinical trial on natural antifungals are very high because antifungal agents will only be used on a very small number of patients. The costs of development of a natural product as a drug often exceed the potential return on investment that should be under consideration. (7) Development of natural products as antifungal is not a financially viable option for pharmaceutical companies because no. of patients suffering from fungal infection is not very large in a particular geographic region, and a handful of natural products-based pharmaceutical companies are available in this field. (8) A trouble in the manufacturing of natural products as a drug problem is that the processing plants do not necessarily maintain the same level of consistency in products used in proprietary drug manufacturing and quality control. (9) There is also a difference in phytochemical constituents due to seasonal and geographical variations, and a huge variation in results among other batches of the same product from the same manufacturer is also observed.

Conclusion

To understand the drug safety issue, the entire research community engaged in natural product research, including researchers in institutes/universities, small/medium-scale enterprises, and pharma companies, must work together to strengthen research in this field. As a final perspective, researchers have to overcome the above-discussed challenges at the level of clinical trials of plant-derived antifungal agents.