Piperine: A spice molecule that serves as a highly effective bioenhancer for TB-antibiotics

Abstract: Tuberculosis (TB) is a transmissible lung disease caused by the bacterium Mycobacterium tuberculosis. Despite advances in medicine, TB still remains a deadly disease due to the generation of multi-drug resistant (MDR), extensively drug-resistant (XDR) strains of M.tb. To combat the emergence of drug resistance to TB, innovative anti-tubercular drugs are the need of the hour. Piper nigrum (Black pepper) is a spice plant found in India and other southeast Asian countries. Black pepper is a member of the Piperaceae family, is most often used in Indian cuisine spices. Its pungent smell is caused due to the presence of piperine molecule in pepper fruits, an alkaloid. Scientific validation revealed piperine has been found to be improved bioavailability and bio-efficacy of a myriad of pharmaceuticals, including antitubercular therapies, antibacterial, antifungal, antiviral, and antitumor agents. Even a combination of piperine with anti-tubercular antibiotics enhanced the bioavailability of drugs. Furthermore, piperine holds the potential to reduce drug dosages and their toxicity, perhaps increasing treatment efficacy and costs. Moreover, it reduces the chances of the generation of drug-resistant forms of TB bacteria.

Tuberculosis (TB) is one of the ancient infectious diseases and still causes the second-highest mortality rate throughout the globe. After the invention of antibiotics, although the mortality rate of TB decreased dramatically, it started to increase from the late 1980s due to the generation of antibiotic resistance TB strain. Eventually, it increased with a coinfection of HIV and diabetes and gave rise to a critical situation. Therefore WHO has alerted all over the globe stating a probable outbreak of pandemic circumstances caused by TB. The projected global burden of TB in 2019 revealed that India is having the highest absolute number of drug-resistant patients in the world.

Isoniazide, Rifampicin, Pyrizinamide, and Ethambutal are the main antibiotics of drug sensitive TB. However, in most of the drug resistance cases, Isoniazide and Ripfampicin antibiotics are resistant to first-line TB treatment. In addition, it has been stated that 484000 new cases of rifampicin resistance per year have increased the risk of a pandemic in TB endemic countries [1]. Most importantly, in the present pandemic situation, SARS-CoV-2 virus infection destroys the lungs condition which may be the cause of future activation of TB disease, as 70% of the world population is latently infected with TB bacteria. Therefore, WHO give prioritize to provoke the discovery of new anti-tubular drugs for TB to achieve the END TB program by 2035.

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Pepper as a medicinal plant

Medicinal plants play an important role in supporting the human race providing fruitful therapeutic implications in different diseases in all civilizations. Tracing their active constituents and mechanism of action, nowadays different modern medicines are produced from bioactive compounds of traditional medicinal plants. Spices have become vital additives in food preparation due to their delicious flavor and health advantages. Due to their advantageous pharmacological qualities, they have made their way into a variety of therapeutic formulations.

Among herbs, pepper spices have gained immense attention due to their particular pungency and their fragrance flavor, making them more important and widely consumed spices throughout the globe. Pepper spices plant belong to the Piperaceae family, which are widely distributed across India, Brazil, and Indonesia [2]. The pungent fruits of this plant contain the key bioactive compound piperine, a naturally occurring alkaloid that has been utilized as a traditional healer to treat different acute and chronic bronchitis and lung-related diseases. Piperine is mainly responsible for pepper’s pungency and accounting 98% of total alkaloids in pepper species [3]. Furthermore, piperine has been also demonstrated to have potent antibacterial, anti-inflammatory, analgesic, antifungal, antipyretic, anti-carcinogenic, immune-modulatory, and antioxidant properties, affecting different in vitro and in vivo models of diseases [4].

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Piperine: a bioenhancer molecule for TB antibiotics

Modern research revealed that piperine act as a specific type of molecule called ‘bioenhancer’ which can increase the efficacy of a particular drug or antibiotic against the corresponding pathogen. It also increases permeability at the absorption site by modulating lipid environment and membrane dynamics, And capable to possesses a chemical structure that is appropriate for enzyme inhibition. Piperine has the ability to influence membrane dynamics by interacting with lipids and hydrophobic portions of protein. This enzymatic modification confirms that as steric constraints to enzyme proteins lose their ability in membrane lipids function [3].

Recent investigations revealed that piperine may operate as an efflux pump inhibitor in Staphylococcus aureus bacteria as well as restore the activity of ciprofloxacin in drug-resistant bacteria [5]. It is well known that efflux pumps are molecules that pump out antibiotics or drugs from bacterial cells, reduce the concentration of antibiotics, and enable to kill the bacteria.

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Singh and co-researchers experimented with respect to  Mycobacterium sp. and reported that piperine-based pepper extracted components had a potent anti-tubercular effect on drug resistance Mycobacterium sp. [6]. Interestingly, it was found that piperine had mild antitubercular activity (MIC>3000ug/ml) along with the inhibitory activity of efflux pump in M smegmatis [7]. Consequently, a different research also established that a mixture of piperine and rifampicin could increase the efficacy of the most important TB drug rifampicin. Moreover, the combination of rifampicin and piperine effectively reduced  TB bacterial burden from the host at a much lower concentration of antibiotic rifampicin. According to the report of Hegeto and their groups, the combination therapy of piperine with rifampicin molecule improved the bioavailability of antibiotics in clinically isolated different M.tb strains and acted at a much lower dose than its normal [8].

Piperine - A spice molecule that serves as a highly effective bioenhancer for TB-antibiotics.

Besides, it was also established that efflux process of ofloxacin resistant TB was effectively blocked by piperine molecule and increased the efficacy of ofloxacin; thus reduced its dose to four-fold, indicating a piperine-assisted increase in accumulation of antibiotics across the cell [9]. Furthermore,  a recently published work also disclosed that a reference drug of TB, streptomycin in combination with piperine (25 μg/ml) also effectively inhibited efflux pumps activity against streptomycin-resistant M.tb strains [10].

Dissecting out the mechanism of piperine it was revealed that piperine downregulates efflux pump gene Rv1258c, which eventually increases the bioavailability of standard TB-antibiotic. Moreover, piperine binds with RNA-polymerase of M.tb but the site of binding is different than rifampicin, which influences the synergistic effect with rifampicin.

Due to such wide angel efficiencies, piperine was used in various clinical trials and already passed the phase-III clinical trials in India with the brand name of Risorine; In this drug, 10 mg of piperine has been combined with standard TB-antibiotics 200 mg of Rifampicin and 300 mg of Isoniazid, increasing the efficiency of drugs in susceptible and drug resistance TB regimen [11].

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Immunomodulatory effect of piperine in TB

Apart from the bioenhancing property, Piperine also has different immunomodulatory effects.

During the in vivo experiment in mouse model, piperine was found to act on both innate and adaptive arms of immunity in tuberculosis. It induced the activation of macrophages and increased MHC-II expression. Furthermore, the proliferation of CD4 and CD8 cells was also found in mouse spleenocyte cells with 1 µg/ml of piperine. In the same experiment, it was found that piperine induced the TB-protective Th1 cells in the animal model of TB. As a result, piperine not only improved the antibiotic availability, but also enhanced the antibiotic’s effectiveness in low doses.

Hence it could be seen that the combination therapy of piperine with rifampicin could produce a low dose of rifampicin (10 mg/kg) which delivered similar results as a normal rifampicin dose, while reduced the toxicity level efficiently [12]. Additionally, it also triggered a protective immunological response in the host, which could have an additional impact on standard antibiotic therapy.

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Conclusive Remarks

Therefore, with this extraordinary bioenhancing and immunomodulatory property, it can be presumed that piperine could reduce the time of TB antibiotic therapy. That can lead to a new potential to decrease the risk of drug-resistant TB generation. Furthermore, its immunomodulatory property also induces the host protective response that can give sterility to the host from the bacteria. So, the piperine molecule can be considered as an adjuvant therapy with traditional TB antibiotic regimens. Moreover, the effectiveness of piperine in TB disease allows a huge increase in medication bioavailability. Thus undoubtfully, piperine is a novel drug molecule that helps to eliminate TB and has an immense potential to be incorporated into the TB drug or TB adjunct therapy in the near future.

References

  1. WHO (2020) Global Tuberculosis Report. Published in 24th March 2020 by WHO. Geneva, Switzerland: WHO.
  2. Haq, I. U., Imran, M., Nadeem, M., Tufail, T., Gondal, T. A., & Mubarak, M. S. (2021). Piperine: a review of its biological effects. Phytotherapy Research35(2), 680-700.
  3. Gorgani, L., Mohammadi, M., Najafpour, G. D., & Nikzad, M. (2017). Piperine—the bioactive compound of black pepper: from isolation to medicinal formulations. Comprehensive Reviews in Food Science and Food Safety16(1), 124-140.
  4. Smilkov, K., Ackova, D. G., Cvetkovski, A., Ruskovska, T., Vidovic, B., & Atalay, M. (2019). Piperine: Old spice and new Nutraceutical?. Current pharmaceutical design25(15), 1729-1739.
  5. Khan, I.A., Mirza, Z.M., Kumar, A., Verma, V. and Qazi, G.N. (2006) Piperine, a phytochemical potentiator of ciprofloxacin against Staphylococcus aureus. Antimicrob Agents Chemother 50, 810–812.
  6. Singh, C., Singh, S.K., Nath, G. and Rai, N.P. (2011) Antimycobacterial activity of Piper longum L. fruit extracts against multi drug resistant Mycobacterium spp. Phytomedicine 3, 353–361.
  7. Jin, J., Zhang, J., Guo, N., Feng, H., Li, L., Liang, J., Sun, K., Wu, X. et al. (2011) The plant alkaloid piperine as a potential inhibitor of ethidium bromide efflux in Mycobacterium smegmatis. J Med Microbiol 60, 223–229.
  8. Hegeto, L.A., Caleffi-Ferracioli, K.R., Perez de Souza, J., Almeida, A.L., Nakamura de Vasconcelos, S.S., Barros, I.L.E., Canezin, P.H., Campanerut-Sa, P.A.Z. et al. (2019) Promising antituberculosis activity of piperine combined with antimicrobials: a systematic review. Microb Drug Resist 25, 120–126.
  9. Raja, A., AbdulKapur, M., Fiju, M. and Mohamed Salique, S. (2015) In vitro studies on efflux pump inhibition of Catharanthus roseus and piperine against ofloxacin resistant M. tuberculosis. Int J Pharm Sci Invention 4, 32–37.
  10. Calsavara, L. L., Hegeto, L. A., Sampiron, E. G., Costacurta, G. F., Murase, L. S., Souza, J. V., … & Caleffi-Ferracioli, K. R. (2021). Rescue of streptomycin activity by piperine in Mycobacterium tuberculosis. Future Microbiology.
  11. Patel, N., Jagannath, K., Vora, A., Patel, M., & Patel, A. (2017). A Randomized, Controlled, Phase III Clinical Trial to Evaluate the Efficacy and Tolerability of Risorine with Conventional Rifampicin in the Treatment of Newly Diagnosed Pulmonary Tuberculosis Patients. The Journal of the Association of Physicians of India65(9), 48–54.
  12. Sharma, S., Kalia, N.P., Suden, P., Chauhan, P.S., Kumar, M., Ram, A.B., Khajuria, A., Bani, S. et al. (2014) Protective efficacy of piperine against Mycobacterium tuberculosis. Tuberculosis 94, 389–396.
Bhabani Shankar Das
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Ph.D. Research Scholar at Center for Biotechnology, Siksha ‘O’ Anusandhan University

Mr. Bhabani Shankar Das is a Ph.D research scholar at the Center for Biotechnology, Siksha ‘O’ Anusandhan University, Bhubaneswar, Odisha, India – 751003. He did his B.Tech & M.Tech dual degree in biotechnology from the same University in 2020.

Ashirbad Sarangi
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Mr. Ashirbad Sarangi is a Ph.D research scholar at the Center for Biotechnology, Siksha ‘O’ Anusandhan University, Bhubaneswar, Odisha, India – 751003. He did his M.Phil degree from North Odisha University in Mayurbhanj, Odisha before that he received his MSc. Botany degree from Ravenshaw University in Cuttack, Odisha.

Dr. Debapriya Bhattacharya *
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Assistant Professor at Center for Biotechnology, Siksha ‘O’ Anusandhan University

Dr. Debapriya Bhattacharya is the Assistant Professor at the Center for Biotechnology, Siksha ‘O’ Anusandhan University, Bhubaneswar, Odisha, India - 751003.

Previously he served as CSIR-Pool Scientist at Special Center for Molecular Medicine, Jawaharlal Nehru University, New Delhi, and worked in Tuberculosis Immunology. He  two postdocs in University of Kwazulu Natal, Durban South Africa, and International Center for Genetic Engineering and Biotechnology, New Delhi, and worked on Immunology and Infection Biology. He is the recipient of two flagship extramural grants from UGC and SERB-DST. Other than this he received Bill and Melinda Global Travel Health Grant award twice.

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