Promising Antituberculosis Activity of Piperine Combined with Antimicrobials: A Systematic Review

Abstract

Piperine, a bioactive compound from Piper nigrum and Piper longum, has shown promising activity as efflux pump (EP) inhibitor and as adjunct in treatment of tuberculosis (TB). The present systematic review investigated scientific studies of the activity of piperine against mycobacteria, with a focus on its mechanism of action, drug interactions, and antimycobacterial activity. A broad and rigorous literature search of three electronic databases (PubMed, Web of Knowledge, and LILACS) was performed according to the PRISMA statement. We considered studies that were published up to December 1, 2017. Google Scholar was also searched to increase the number of publications. We searched for articles using the search terms “piperine” and “Mycobacterium spp.” The search yielded a total of 225 articles. After removing duplicate publications, 208 publications remained. Of these, we evaluated the full text of 13 articles. After applying the inclusion criteria, eight studies were included in the present systematic review. The results of the systematic review showed that piperine has promising anti-TB activity, mainly when combined with antimicrobials, and plays an important role as an EP inhibitor.

Introduction

In 2016, 6.3 million new cases of tuberculosis (TB) were reported. TB is the ninth leading cause of death worldwide and the leading cause from a single infectious agent, ranking above HIV/AIDS.¹ Although the incidence of TB is slowly decreasing, roughly one-third of the world's population has been infected by the bacilli.^1,2

Most antibiotics used for the treatment of TB are useless in the short term because of unique characteristics of Mycobacterium tuberculosis. The ideal treatment for TB should kill active bacilli, control latent organisms, and prevent the emergence of resistant strains.³ The current treatment for TB often induces side effects, which is a likely reason why some patients eventually discontinue their treatment before it is completed and resistant strains can arise.⁴

Resistance to anti-TB drugs has been mainly attributed to spontaneous mutations in specific genes of M. tuberculosis. However, efflux pumps (EPs) may also initially impart natural tolerance and resistance to one or more compounds.^3,5–8

The antimicrobial activity of natural products is a research area with great potential for the development of new technologies to combat TB especially in countries that have wide biodiversity, such as Brazil and India.⁹

Piperine (PIP) is a bioactive compound of Piper nigrum and Piper longum and possible alternative for the treatment of TB. Studies have suggested that it is an efflux pump inhibitor (EPI) and may increase the efficacy of some antimicrobials.^10–12 PIP has also been reported to have antiinflammatory,¹³ antimicrobial,^14,15 antifungal,¹⁶ analgesic, antipyretic, antioxidant,^17,18 and anticarcinogenic effects.¹⁹ It may also be able to increase the bioavailability of some drugs^20–22 and increase the activation of detoxification enzymes.²³ Our research question was whether piperine has some antimycobacterial activity. Could piperine potentiate the effect of antimicrobials? Thus, we investigated the activity of PIP against mycobacteria, with a focus on its mechanism of action, drug interactions, and antimycobacterial activity by a systematic review.

Methods

We performed rigorous search in electronic databases according to the PRISMA statement²⁴ using the search terms “piperine” and “Mycobacterium spp.” (See Supplementary File 1; Supplementary Data can be viewed online at www.liebertpub.com/mdr).

Data sources and research

We searched the PubMed, Web of Knowledge, and LILACS databases for articles that were published up to December, 2017. A flowchart of the search is presented in Fig. 1.

FIG. 1.

Data search and extraction (PRISMA flowchart).²⁵

To identify target publications in PubMed, Medical Subject Heading (MeSH) terms were applied. Six independent researchers (Group 1: L.A.H., J.J.V.T, A.L.A., S.S.N.V., I.L.E.B., and P.H.C.) conducted searches to define and identify the largest number of MeSH terms to ensure high sensitivity for identifying relevant scientific publications. All disagreements were resolved by consensus (Supplementary File 2). One expert (J.J.V.T.) was invited to ensure MeSH terms quality and accuracy. In the first phase of the study, the researchers from Group 1 focused on the titles and abstracts of the publications that were identified in each database. In PubMed, the MeSH terms were organized into three blocks: block 1 (“Tuberculosis” OR “Mycobacterium” OR “Gram-Positive Bacteria”), block 2 (“Piper” OR “Antitubercular” OR “Piperidines” OR “Polyunsaturated Alkamides/Pharmacology” or “Benzodioxoles”), and block 3 (“ATP-Binding Cassette Transporters” OR “Multidrug Resistance-Associated Proteins” OR “Gene Expression Regulation, Bacterial”). For the Web of Knowledge database, a Topic Search was applied, which ensured the sensitivity of the search. In the LILACS database, we searched “Piper/química” and “Mycobacterium.” Other publications were retrieved in Google Scholar using free terms, and relevant articles were selected.

Inclusion and exclusion criteria

Studies that evaluated the PIP and Mycobacterium spp. interactions were included in the study (Supplementary File 3). Using database filtering features and by manually checking the abstracts, publications were validated. Published English, Portuguese, or Spanish articles up to December 1, 2017, either in vitro or in vivo assays, were included.

Reviews, comparative studies, case reports, editorials, editors' comments, news, guidelines, and interviews were excluded (Fig. 1). Articles with no mention about PIP activity against Mycobacterium spp. in their summaries/abstract were also excluded (Supplementary File 4).

Evaluation of quality

The second phase of the present systematic review was to evaluate the selected abstracts publications screened. The full-text articles were retrieved in PDF format, randomly arranged and distributed to the six independent researchers from Group 1 for validation to avoid bias with regard to interest and selection. Disagreement concerning the inclusion or exclusion was solved by consensus. In the third phase, the selected articles were randomized and distributed to five independent judges (Group 2: R.F.C., K.R.C.-F., R.B.L.S., V.L.D.S., and P.A.Z.C.-S.). The final number of publications (n) reflected the quantitative and qualitative aspects of the articles that were determined by consensus among Groups 1 and 2. To increase the breadth of the present review, the bibliographies of the selected articles were also searched to identify original articles that might not have been retrieved in the previous search phases.

Data extraction

With support from a specialist (J.J.V.T.), Group 1 researchers extracted data from the selected articles. The characteristics of the studies that comprised the systematic review were highlighted, including authors, year, Mycobacterium species, susceptibility profile, sample type, and methods, and a table was constructed to display these characteristics. After consensus was reached among the researchers from Group 1, the researchers from Group 2 also analyzed the table. Group 2 independently validated the publications. Disagreements among Groups 1 and 2 were solved by consensus.

Results and Discussion

To our knowledge, this is the first systematic review that addresses PIP activity in mycobacteria, focusing on its mechanism of action, drug interactions, and antimycobacterial activity. Although a meta-analysis would be relevant to evaluate the subject, the publications selected for this systematic review did not present the adequate profile to perform this method.

The initial database search yielded 225 articles that were identified using the keywords predetermined by the researchers from Group 1. After removing duplicate articles, 208 remained. Of these, the full texts of 13 articles were evaluated. Eight of these met the established inclusion criteria.

Most of the studies were performed with Mycobacterium spp. clinical isolates and reference strains, conducted in India and published from 2001 to 2012. The main objectives of these studies were to evaluate the minimum inhibitory concentration (MIC) of PIP, time-kill curves, synergism, and the inhibition of EPs (Table 1).

Table 1.

Characteristics of Included Studies

Reference	Mycobacterium species	Strains profile	Sample	Methods for evaluation	Main findings of PIP	Conclusion
Sharma et al.³⁵	Mycobacterium tuberculosis H₃₇Rv (ATCC 27294)	Pan-susceptibility	BALB/C infection; culture	Cell proliferation assay; cytokine estimation by ELISA; MØ nitrite production—Griess. Protective efficacy of PIP in mice infection: (1) FC; (2) VCFUC; (3) RT-qPCR	Modulates the Th1 response, increases lymphoproliferation and NO production by MØ; The combination PIP + RIF showed a 1.4-0.8 log reduction on bacterial load at mice lungs, when compared to RIF alone.	The upregulation of Th1 immunity by PIP can be synergistically combined with RIF to improve its therapeutic efficacy in immunocompromised TB patients.
Jin et al.²⁸	Mycobacterium smegmatis mc2 155 (ATCC 700084)	Pan-susceptibility	Culture	EtBr accumulation and efflux assay; MIC determination; modulation assay.	PIP had a moderate antimycobacterial activity compared with the other positive-control EPIs (RES, CHL, VP, CCCP); exhibited a stronger EtBr efflux inhibitory effect in M. smegmatis.	PIP was shown to be a potential inhibitor of the intrinsic EP system in mycobacteria.
Sharma et al.¹²	M. tuberculosis H₃₇Rv (ATCC 27294), RIF-resistant mutant and MDR clinical isolate	Pan-susceptibility, RIF resistant and MDR	Clinical isolates; culture	Checkerboard; TK; selection of resistant mutants in vitro; postantibiotic effect; RT-qPCR analysis of putative EP protein; DS	PIP reduced the MIC and improved the bactericidal activity of RIF in all bacilli tested; in the presence of RIF, M. tuberculosis RIF-R showed a 3.6-fold overexpression of Rv1258c.	PIP plays a significant role in the inhibition of Rv1258c and may be useful in augmenting the antimycobacterial activity of RIF in a clinical setting.
Rukachaisirikul et al.³¹	M. tuberculosis (H₃₇Ra strain)	Pan-susceptibility	Culture	MABA	Chabamide (PIP dimer) exhibited antituberculosis activity against M. tuberculosis.	The novel PIP dimer, named chabamide, isolated from stems of P. chaba has antituberculosis activity.
Balakrishnan et al.²⁹	M. smegmatis mc2155	RIF resistant and susceptibility	Culture	VCFUC; evaluation of RNA polymerase activity.	The combination of RIF + PIP caused a complete inhibition of growth of M. smegmatis. The mix completely abolished the transcriptional activity of RIF-R RNA polymerase.	PIP enhances the binding ability of RIF to RNA polymerase.
Singh et al.²⁶	M. tuberculosis GN/mt-75, M. smegmatis GN/ms-43	MDR	Clinical isolate	MIC: different dilutions into Müeller-Hinton broth medium and Löwenstein-Jensen.	PIP was more efficient against M. tuberculosis than M. smegmatis.	PIP has activity against the multidrug resistant strains of Mycobacterium, especially M. tuberculosis.
Patilaya et al.³⁰	M. tuberculosis H₃₇Rv ATCC 25618	Pan-susceptibility	Culture	TEMA; TKC; scanning electron microscopy	Ethylacetate fraction of Piper nigrum containing PIP reduced the CFU count and caused significant morphological changes during the 7-day period study.	The ethylacetate fraction of P. nigrum leaf has potential activity against M. tuberculosis.
Raja et al.²⁷	M. tuberculosis	Resistant to ofloxacin	Clinical isolates	MABA; checkerboard	PIP showed potent antimycobacterial activity, and EP inhibits activity against M. tuberculosis.	The bioassay of PIP showed potent anti-TB activity.

CCCP, carbonyl cyanide m-chlorophenyl hydrazone; CFU, colony-forming unit; CHL, chlorpromazine; DS, docking studies; ELISA, enzyme-linked immunosorbent assay; EP, efflux pump; EPI, efflux pump inhibitor; EtBr, ethidium bromide; FC, flow cytometry; Ly, lymphocyte; MABA, microplate Alamar blue assay; MDR, multidrug resistant; MIC, minimum inhibitory concentration; MØ, macrophages; NO, nitric oxide; PIP, piperine; RES, reserpine; RIF, rifampicin; RIF-R, rifampicin resistant isolates; RT-qPCR, reverse transcription quantitative polymerase chain reaction; TB, tuberculosis; TEMA, tetrazolium microplate assay; TK, time-kill curve; VCFUC, viable colony-forming unity count; VP, Verapamil.

Minimum inhibitory concentration

Seven of the eight articles selected evaluated the antimycobacterial activity of PIP or its effects in combination with other antimicrobials. The studies tested the activity of PIP that was obtained from different extracts and reported MICs that ranged from 50 to >100 μg/mL against the M. tuberculosis reference strain H₃₇Rv and higher (e.g., 3,000 μg/mL) for Mycobacterium smegmatis.²⁶

Raja et al.²⁷ tested six ofloxacin (OFL)-resistant M. tuberculosis isolates, by microplate Alamar blue assay (MABA), which showed PIP MIC 50 mg/L. Singh et al.²⁶ tested different extracts obtained from the fruit of Piper longum L., by a modified Kirby-Bauer disk diffusion method, and found that M. smegmatis GN/ms-43 inhibition growth were 12.33 ± 0.57, 15.66 ± 1.52, and 11.66 ± 0.57 mm for the chloroform, ethyl-acetate, and methanol fractions, respectively. This preliminary assay revealed that the ethyl-acetate fraction had the best inhibitory activity against M. smegmatis. Piperine crystals were purified from the ethyl acetate fraction and showed MICs 3,000 and 39 mg/L, in multidrug-resistant M. smegmatis GN/ms-43 and M. tuberculosis GN/mt-75, respectively. Other gram-negative and -positive bacteria were tested, and growth inhibition was observed (MICs ranged from 14 to 180 mg/L). Working with the reference strain M. smegmatis mc² 155, Jin et al.²⁸ found that PIP had moderate antimycobacterial activity (MIC 128 mg/L) by broth dilution. On the contrary, Balakrishnan et al.²⁹ observed no significant inhibitory activity of PIP against M. smegmatis, despite having tested concentrations up to 50 mg/L.

By tetrazolium microplate assay, Patilaya et al.³⁰ showed that n-hexane, ethyl-acetate, and water leaf extracts of P. nigrum had activity against M. tuberculosis H₃₇Rv with MICs 50, 25 and 100 mg/L, respectively. Sharma et al.¹² evaluated the activity of PIP against two M. tuberculosis isolates (one rifampicin monoresistant and one multidrug-resistant) and the reference strain H₃₇Rv and found MICs >100 mg/L for both of the isolates. Rukachaisirikul et al.³¹ tested a dimer of PIP (chabamide) obtained from n-hexane fraction of Piper chaba Hunter and found a MIC 12.5 mg/L against M. tuberculosis H₃₇Rv.

According to Gu et al.³² crude extracts that have MICs ≤128 mg/L and pure compounds with MICs ≤64 mg/L are promising and warrant further studies of their antimycobacterial activity. The studies that were included in this systematic review showed that PIP alone has low antimycobacterial activity. Studies that evaluated the effects of PIP and its structural analogs on other bacteria, such as Staphylococcus aureus, have reported similar results, with MICs >100 mg/L.¹⁰

Time-kill curve assay

Among the selected articles, only two evaluated the actions of PIP using time-kill assay. Patilaya et al.³⁰ evaluated the effects of an ethyl-acetate fraction of P. nigrum in M. tuberculosis H₃₇Rv and observed a marked decrease in colony-forming units (CFUs) on day 2 of PIP exposure. The CFU continued to decrease until on day 5 and remained stable to the end of treatment, showing a 98.92% reduction in CFU compared with the control group not exposed to PIP. Sharma et al.¹² performed a time-kill curve assay with exposure of a PIP and rifampicin (RIF) combination also observed reduction in CFU.

Drugs combinations studies and efflux extrusion

Considering PIP has low antimycobacterial activity, some studies have evaluated its activity combined with antimicrobials. Sharma et al.¹² tested the effect of PIP plus RIF, by checkerboard assay, and found four- and eightfold reductions of RIF MIC against H₃₇Rv and RIF-resistant isolates, respectively. Also, observed PIP acts as EPI, once ethidium bromide (EtBr) MIC decreased 8- and 32-fold in M. tuberculosis H₃₇Rv and in a RIF-resistant M. tuberculosis isolate, respectively. EP extrusion is the only known resistance mechanism of EtBr.¹² Similar results were reported by Jin et al.²⁸ with two- and fourfold reductions of the EtBr MIC in M. smegmatis mc² 155. The ability of PIP to reduce the EtBr MIC was comparable to the effects of chlorpromazine and reserpine, which are known to be EPIs, and was in a concentration-dependent manner.²⁸

Sharma et al.¹² tested the effects of RIF (0.5 mg/L) combined with PIP (25 mg/L) in M. tuberculosis H₃₇Rv and observed a >3-log reduction in CFUs on day 8 of treatment, whereas RIF alone had a similar effect only at a higher concentration (1 mg/L). Considering the concentration-dependent effect of RIF, the RIF plus PIP combination appears to be promising to combat the bacillus. In the same study, the Rv1258c-induced gene expression upon exposure to RIF, determined by quantitative real-time polymerase chain reaction, was observed in resistant M. tuberculosis isolate. The authors suggested, after applying molecular docking model study that PIP may bind to the protein coded by this gene. PIP was shown to bind to the Arg141 residue of the protein with greater affinity, among other possible interactions. The authors suggested that such binding may be responsible for the RIF-induced inhibition of efflux out of the cell by the Rv1258c EP. Consistent with this finding, a previous study by our group found Rv1258c overexpression that was induced by exposure to 0.5 × MIC of RIF plus verapamil in M. tuberculosis H₃₇Rv. Verapamil is a well-known EPI that is used as a positive control in studies that develop new EPI molecules.^33,34

Raja et al.²⁷ observed a fourfold decrease in the OFL MIC when combined with PIP in six OFL-resistant M. tuberculosis isolates. These results seemed to us that PIP has synergic activity with other drugs by acting as an EPI. Similar results were found when PIP was combined with another fluoroquinolone, ciprofloxacin, in S. aureus.^10,11 The combination of PIP with extracts of Catharanthus roseus L. resulted in a fractional inhibitory concentration index 0.06 in M. tuberculosis.²⁷

Another action of PIP combined with RIF is its ability to completely inhibit the transcriptional activity of RNA polymerase in M. smegmatis mc² 155 and in a RIF-resistant strain. To characterize this inhibition, a molecular docking study was performed using RNA polymerase structures from Thermus aquaticus and Escherichia coli. Both, RIF and PIP, can be accommodated in the binding pocket of the RNA polymerase enzyme by stacking, which may enhance the inhibitory activity of RIF mainly in RIF-resistant M. tuberculosis isolates.²⁹

Scanning electron microscopy

Patilaya et al.³⁰ performed a scanning electron microscopy study of M. tuberculosis H₃₇Rv cells exposed to ethyl acetate fraction of P. nigrum containing PIP. They observed slim, shrunken, wrinkled, and empty bacilli after day 2 of exposure. The cells also appeared to stick together because of the presence of a “web-like mess,” which might have been attributable to the release of the cytoplasmic contents of ruptured cells. In a similar study, Caleffi-Ferracioli et al.³³ observed the same morphological changes in M. tuberculosis cells (i.e., wrinkled and rounded cells) after exposure to 0.5 × MIC of verapamil. These morphological changes that were induced by PIP and verapamil are probably attributable to their ability to inhibit bacterial EPs.

Postantibiotic effects and immunological modulation by piperine

The postantibiotic effect of RIF alone and combined with PIP in M. tuberculosis H₃₇Rv was investigated by Sharma et al.¹² They found that 1 mg/L PIP concentration dependently prolonged the postantibiotic effect of RIF from 48 to 72 hr. Sharma et al.³⁵ also investigated the immunological effects of PIP in vitro and in vivo. For the in vitro analysis, T and B lymphocytes were extracted from the spleen and peritoneal macrophages in BALB/c mice. The in vivo analysis used cells from mice that were infected with M. tuberculosis H₃₇Rv. The in vitro study found that PIP significantly increased the proliferation of T and B lymphocytes, increased the production of Th1 cytokines (i.e., interferon-γ [IFN-γ] and interleukin-2 [IL-2]), did not alter the Th2 response (i.e., IL-4) in lymphocytes, and significantly increased the production of nitric oxide in macrophages. PIP increased the production of IFN-γ and IL-2 in lymphocytes in mice that were treated with PIP before and after infection, did not alter IL-4 production, significantly increased the CD4+ and CD8+ cell populations, reduced the number of CFU in the lungs in treated mice, and caused a twofold increase in the gene expression of IFN-γ and IL-2.³⁵

Conclusion

The findings of this systematic review showed that PIP plays an important role in the inhibition of EPs and modulates the immune system, especially when combined with other anti-TB drugs (e.g., RIF). The mechanisms of action of PIP should be further explored to develop possible alternative treatments for TB.

Strengths and Limitations

The present systematic review searched three databases and Google Scholar. This strategy allowed us to increase the sensitivity and accuracy of the publications that were retrieved. The main findings were analyzed and organized in a table based on consensus by the researchers. The relatively few number of publications on the topic hinders wider discussions and definitive conclusions. However, the inclusion of articles that were published in English, Portuguese, and Spanish helped increase the range of the study.

Drug efflux systems in mycobacteria are a worthy area of investigation that may allow the development of new therapeutic options for TB with greater safety and efficacy. PIP, the bioactive compound that is contained in P. nigrum and P. longum, is a promising EPI and has beneficial effects on several other biological processes.

Footnotes

Acknowledgments

We thank the Brazilian Coordination for the Improvement of Higher Education (CAPES) by the actions of support directed to postgraduation.

Disclosure Statement

No competing financial interests exist.

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