Since prehistoric time, medicinal plants and herbs have been discovered and used in folk medicine (Stojanoski 1999). Now phytocompounds are at the forefront of drug discovery. According to World Health Organization (WHO), “Any plant whose one or more part, contain substance that can be used for therapeutic purpose or which is a precursor for synthesis of useful drugs” is classified as medicinal plant. WHO has estimated that about 80% of the World population rely almost exclusively on traditional medicine for their primary healthcare needs (Farnsworth 1988). Medicinal plants are the “backbone” of traditional medicine system, and most of the people in the less developed countries utilized these traditional medicinal plants on a regular basis (Davidson-Hunt 2000) for their well-being. Plants produce or secrete an array of chemical compounds and use them for various biological functions including defense against insects, fungi and bacteria. Scientists are now exploring these phytocompounds as novel therapeutics approach to solve the emerging issues of multi-drug resistance (Rolta et al. 2020b; Rolta et al. 2021; Salaria et al. 2021). Antimicrobial resistance is a major threat to animal and human health development, affecting our ability to treat a range of infections. Treatments for a growing number of infections have become less effective in many parts of the world due to emergence of drug resistance (WHO 2016). Among many other diseases, candidiasis caused by Candida albicans is one of the major concerns (López-Martínez 2010). Fluconazole and amphotericin B are the most commonly and widely used antibiotics to treat Candidiasis. Some strains of Candia have developed resistance (antifungal resistance) to these antibiotics and are difficult to treat (Helmerhorst et al. 1999). The rise of antifungal resistance is very high and discovery of new antibiotics is very slow. Centres for disease control and prevention (CDC) has reported that some strains of Candida are highly resistant to even first line and second line of antifungal medications, such as fluconazole and the echinocandins (anidulafungin, caspofungin, and micafungin). Candida auris has been reported to be resistant to fluconazole and amphotericin B and now it has become a serious health concern (Satoh et al. 2009; Lockhart et al. 2016). The individual with drug resistant infection has to consume higher dosage of antibiotics, which in turn leads to emergence of drug resistance and also responsible for many side effects and ultimately life expectancy (Gould et al. 2013). The mechanisms of antibiotic resistance in mainly due to mutation in gene encoading the target site of FQs (DNA gyrase and topoisomerase IV), over expression of efflux pumps and protection of the FQ target site by a protein designated Qnr (Munita and Arias 2016). The combination therapy of two or more antibiotics (synergism) has been in practice for some, but this has also resulted in selection pressure on pathogens and drug toxicity (Dudhatra et al. 2012).
Therefore, the current need is to search for molecules that are not antibiotics itself, but enhance the potency /availability of the antibiotics. Such molecules should be non-toxic and enhance the bioavailability of antibiotics in combination and act synergistically. Potent bio-enhancers could potentially lower the dosage of antibiotics and therefore reduced toxicity to the host. Phytochemicals of medicinal plants have huge potential to be developed as bio-enhancer of antibiotics and feed the drug discovery pipeline to develop new therapies to manage candidiasis. India has huge diversity of medicinal plants and rich system of traditional medicines and ethno pharmacology. Especially, Himalayan region houses 1748 species of unique medicinal plants with various traditional and modern therapeutic uses (Samant et al. 1998), including 675 species of wild edible plants (Samant and Dhar 1997) and 118 species of medicinal plants yielding essential oils. High altitude of Himalayas is a unique habitat that resulted in the accumulation of unique phytoconstituents in medicinal plants and warrants their exploitation in a holistic manner to counter the problem of multidrug resistance and for the well-being of people. The Indian sub-continent is suitable for cultivation of large number of medicinal and aromatic plants, which can be used as raw materials for pharmaceuticals, perfumery, cosmetics, flavors and food. The Chanshal valley of Himachal Pradesh is regarded as hub of medicinal plants and trees. It contains several species of medicinal plants and trees e.g. Rheum emodi, Juniperus communis, Bistorta macrophylla, Jurinea macrocephala, Picrorhiza kurroa, Pleurospermum bruninis and Betula utilis etc. and people of Dodra Quar and Rohru region utilize these medicinal plants or trees for the cure and preventions of different diseases (Jaundice, wound healing, fever, cough, respiratory problems, boils, nerve disorder, dysentery ulcers etc.) since ancient time.
B. macrophylla is one of the important and unexplored medicinal plant species of alpine region of Himalayas and is commonly known as Kukhri, Chhotaninayin, Kande-re-ninai in Hindi and Snakeweed in English. B. macrophylla belongs to family polygonaceae. B. macrophylla is a stout perennial herb and arise from a woody root stock (rhizome), reticulate. It is native to mountain regions of West-China, Pakistan, Bhutan, North India (Himachal Pradesh, Uttarakhand), West India (Western Ghats) and Nepal (Chauhan 1999). In India, it is distributed at altitudes ranging from 3300 to 3800 meters height in the temperate and subtropical regions of Himalayas (Chauhan 1999). Rhizomes of B. macrophylla are widely used in Ayurvedic and traditional medicine as antidiarrheal, antidysenteric, alleviates stomach pain, anti-inflammatory, and anti-pyretic (Gaur 1999). Traditionally, B. macrophylla is used to cure the stomach problems and paste of B. macrophylla rhizome is given to children and infants for stomach problems. Older patients chew the roots for the same problem (Chauhan 1999). Paste and powder of B. macrophylla roots was taken orally to cure fever, ulcer and toothache. Paste of B. macrophylla roots by prepared by rubbing roots on hard surface of stone with few drops water. It is also used to cure tuberculosis, inflammation, pyretic fever, flu, lungs disorders, diarrhea, vomiting, arthritis, gout, kidney stones or hyperacidity and hypertension (Wangchuk et al. 2016). B. macrophylla is known for its traditional medicinal values, but not explored scientifically, except one report by Chandra et al. (2016). Therefore, the current study was designed to study the potential of methanolic extract of rhizome of unexplored B. macrophylla as bioavailability enhancer of fluconazole and amphotericin B against to manage candidiasis and identify the major phytocompounds by GC-MS analysis.