EFFLUX PUMP INHIBITORS: ENHANCE THERAPY AND CAUTERIZE TUBERCULOSIS
HTML Full TextEFFLUX PUMP INHIBITORS: ENHANCE THERAPY AND CAUTERIZE TUBERCULOSIS
Gyanendra Singh* and A. K. Srivastava
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, (Banaras Hindu University), Varanasi - 221005, Uttar Pradesh, India.
ABSTRACT: The requirement of drug resistance regularly to plague Tuberculosis control, with vast increase in the spreading of MDR-TB. It can act as a gateway to XDR-TB and then emphasis on the urgency for new drug development and optimal treatment option for Tuberculosis therapy. In this study, we assess the recommending for using Rifabutin (RFB) instead of rifampicin (RIF). The objective of this study and built to shortening and efficient treatment time. This mechanism is resistance result in an efflux of various anti TB drugs from the infected bacterial cell, resultant decreasing the intracellular drug in the bacterial cell. Bacillus reverts the antibiotic treatment ineffective. Mycobacterial efflux pumps may have originally served to protect against environmental toxins, in the pathogenic mycobacteria they seems to have been repurposed for intracellular growth. On the above fact, we discuss the potential of efflux pump inhibitors such as either natural or synthetic to shorten tuberculosis treatment by their dual inhibition of resistance and growth. It has significant clinical implications, especially in MDR-TB management where treatment options are extremely limited.
Keywords: |
Tuberculosis, Co-infection, Efflux pump inhibitor, Rifabutin, Mycobacterium tuberculosis, MDR/XDR
INTRODUCTION: Major challenges in current tubercular therapy management are the long duration of treatment required for Antitubercular drug minimum for six months. Only cell wall barrier is not sufficient to show the intrinsic drug resistance of tubercular bacteria. Rifampicin and Rifabutin are two rifamycin derivatives which are widely used for the treatment of tuberculosis, especially in pulmonary tuberculosis 1. In addition to that the being more active than rifampicin against Mycobacterium tuberculosis (in-vitro), rifabutin has been approved to be curing with chronic drug and Multi-Drug resistance in pulmonary tuberculosis 2. Moreover, the result of these drugs in clinical trials in patient with infection of HIV has prescribed Rifabutin for prophylaxis of Mycobacterium avium complex (MAC) Mechanism which causes of death in AIDS 3.
Drug Efflux Pump in MDR Tuberculosis: Drug efflux is one of the important factors of contributes intrinsically and acquired resistance in Tuberculosis bacteria 4. Drug efflux transporters in bacteria lie into five broad categories, such as the major facilitator superfamily (MFS) and the multidrug and toxic extrusion, resistance-nodulation-cell division, Small Multidrug Resistance (SMR) and ATP-banding cassette (ABC). All of the categories mentioned above of drug efflux transporters which are recognized as genome sequences of various mycobacteria with M. Tuberculosis (http://www.sanger.ac.uk/Projects/ M. tuberculosis) 5. Drug efflux pumps have been described in several mycobacteria till to date.
Some examples, M. smegmatis LfrA and MFS transporter compatible to the QacA for a multidrug efflux pump of Staphylococcus aureus, where it was the first multidrug efflux pump reported 6. When expressed on a plasmid, LfrA mediates low level resistance to fluoroquinolones and other toxic compounds such as ethidium bromide. Another three efflux pumps in the category of MFS reported for various mycobacterial species as EfpA, Tap, and P55 can also know to generate low level resistance with these exporters when they expressed from plasmids. The role of drug exporters in intrinsic drug resistance of Mycobacteria 7.
Classes of Bacterial Efflux Pump Inhibitors: The efflux pump plays a key role in the treatment of M. tuberculin infection where the drug resistance exit of efflux activity in the anti-tubercular drug. Rifabutin has recently been included in new regimens for treatment therapy with the aim of improving and reducing treatment periods. Efflux-mediated resistance to rifabutin, as well as efflux-mediated cross resistance to efflux pump inhibitors. However, recent studies have highlighted the ability of the efflux pump inhibitor Piperine, verapamil, etc. to decrease the MIC of anti-TB drugs, thereby diminishing the toxic effect and enhancing treatment. Also, cross resistance to efflux pumps inhibitors seen through reversed treatment of rifabutin 8.
It is a high complex method to design appropriate treatment regimens through available anti-tubercular drug for MDR-TB and XDR-TB. This has required for the new drug development and expedites progress to the new combination and regimen development 9. Now, efflux pump inhibitors have been known as putative novel compounds as drugs, since they have the ability to partially restore susceptibility to anti-TB drugs by inhibiting the activity of efflux pumps.
This preparation requires the presence of the efflux pump inhibitor with the anti-TB drugs at sub-inhibitory concentrations. There are several types of efflux pump inhibitors with different methods of actions that can be either vast or peculiar to a single class of efflux pump 10.
Few common pump efflux inhibitors are:
Calcium (Ca21) Channel Blockers: Most common efflux pump inhibitor in this category is verapamil and phenothiazines which reduce the activity of trans-membrane potential. According to the IVIVC studies, it has already proven that these compounds prevent the activity of efflux pumps belongs to the Major Facilitator Superfamily (MFS) in mycobacteria 11.
Verapamil: It comes in the phenyl alkamine prototypes class. It is used for the treatment of various cardiac disorders, headaches and migraines. It acts as precursors of vesicular monoamine transporters and P-glycoprotein in the membrane cell. While in prokaryotes its acts as an inhibitor for ATP dependent multidrug transporters and MDR pumps by interfering with the PMF. Significantly it also shows inhibitory effect on susceptibility to rifampicin and rifabutin in MDR-TB 12.
Phenothiazine: It is tricyclic compound of derivative including chlorpromazine, piperidine and thioridazine which are commonly used as antipsychotic and antihistaminic compounds. In this category, these derivatives are big inhibitors of K+ transport and Ca2+ channels, with higher ability to reverse the MDR-TB phenotype in M. Tuberculosis. They also inhibit the proton-motive force (PMF)- dependent (MFS) pumps by reducing trans-membrane potential. Recent studies have explored that thioridazine and chlorpromazine prevent ethidium bromide efflux from M. smegmatis and M. avium complex. Moreover, both compounds have also proven to suppress clarithromycin and isoniazid resistance in M. tuberculin complex with expediting the intracellular killing of phagocytized of M. tuberculosis in spite of increasing the efficacy the potency of these compound might result in an increased cytotoxicity, thus limiting their use clinically 13.
The Protonophores: It includes carbonyl cyanide m- chlorophenylhydrazone (CCCP), 2, 4-dinitro phenol (DNP) and valinomycin inhibit efflux pump activity by decreasing the trans-membrane potential. IVIVC correlation studies have explained these compounds inhibit the activity of efflux pumps belonging to the MFS in mycobacteria. CCCP and DNP disperse the membrane PMF with the advancement of the trans-membrane electrochemical potential; thus, these compounds may be toxic to the cells. Also of this protonophores are also known as ionophores, and they work as chemical inhibitors of oxidative phosphorylation, serves to inhibit the activity of ATP synthase; therefore, CCCP and DNP have an effect on ABC superfamily pumps 14.
Valinomycin: This is a compound that decreases the electrochemical gradient which can be generated by K+. Valinomycin is a potassium-specific efflux pump inhibitor highly sensitive for Na+ and K+. It helps the movement of K+ through lipid membranes ‘down’ an electrochemical potential gradient and targets the MFS and ABC super family 15. Valinomycin shown to inhibit the P55 efflux pump, which relies on trans-membrane proton and electrochemical gradient as source of energy for the active export of compounds in M. tuberculosis. Microarray analysis of M. tuberculosis strains treated with valinomycin showed a significant decrease of p27 and p55 expression levels, therefore suggested efflux mediated drug resistance. The treatment of naturally Pyrazinamide resistance M. smegmatis with Valinomycin showed an increase in the accumulation of pyrazinoic acid at neutral pH, illustrating the role of efflux activity in the Pyrazinamide resistant phenotype 16.
Efflux Pump Inhibitor Originate from Plant: In addition to inhibit multidrug transporters, alkolides obtains from different parts of various plant (efflux pump inhibitors) are emerging adjutants used for synergistically improve the potency of some anti-TB drugs. Such alkaloids includes: the plant alkaloids reserpine; piperine, the trans-trans isomer of 1-piperoyl-piperine from the piperacy family; and berberine, from the berberidaceae family 17.
Reserpine: It is naturally occurring compound that was originally isolated from the roots of Rauwolfia vomitoria (Afz). Mechanism of reserpine is to blocking irreversibly from uptake and storage of dopamine from synaptic vesicles or inhibiting the vesicular monoamine transporters. Reserpine widely used for the treatment of hypertension and Psychiatric disorders prescribed daily dose not more than 25mg due to potential adverse effects. It targets the efflux pumps of RND superfamily, MFS and membrane protein class that’s why it considered being promising efflux pump inhibitors 18. It also reported that the reserpine enhance the potency of drug treatment therapy in TB when it is added with amino acids. This is the special feature of some efflux protein transporter. A case of the last co-operation is that of reserpine and Bmr protein, an individuals from MFS transporters that is responsible for tetracycline efflux in Bacillus subtilis 19.
Piperine: Piperine is present in black pepper and can be isolated from pipernigrum. It was utilized as a part of antiquated circumstances in a few types of conventional medication. Piperine is a drug Potentiator that represses the human P-glycoprotein, particularly cytochrome P450- mediated pathways, and mediates inhibition of glucuronidation activity in animal models. Piperine is utilized financially as inhibitor of enzymes that are vital both in drug digestion and in the carrying of metabolites and xenobiotics. It all the while expands the bioavailability of different compound and lessens the adequacy of a few medications. Investigations of piperine and piperidine recommend an inhibitory activity against dynamic bacterial efflux pumps, incorporating those in mycobacteria 20.
A review directed in M. smegmatis demonstrated that piperine (32mg/L) could diminish the minimum inhibitory concentration (MIC) of ethidium bromide by 2-folds, along these lines showing piprine’s to repress mycobacterial efflux pumps. These examinations have empowered more reviews concentrating on the impact of this efflux pump inhibitor in M. tuberculosis where the defensive adequacy of piperine in the blend with rifampicin (1mg/kg) was tried. Piperine was synergistic with rifampicin treatment, bringing about the 6-ovelap diminish in lung cfu, along these lines enhancing the adequacy and efficacy of rifampicin 21. These discoveries have clinical ramification for the treatment therapy of immuno-compromised TB patients. Notwithstanding the set number of studies in mycobacteria, piperine has been appeared to be compelling in other pathogenic bacteria. For example, the MIC of ciprofloxacin was lessened 2-folds for a NorA-overexpressing staphylococcus aureus strain within sight of piperine 22.
Berberine: Berberine is a nucleic acid binding isoquinolone alkaloid exhibiting broad-spectrum therapeutic properties that was isolated from Berberis fremontii. Studies on berberine have preliminary focused on its bacterial effects on the cardiovascular system, its anti-inflammatory properties and its ability to suppress the growth of different tumour cell in cancer. It is also used to treat neuro-inflamation associated disorders. Berberine was previously suggested to have week antibacterial activity when acting alone; however, it has been shown to have a synergistic effect when used in combination with other compounds such as 5’methoxyhynocarpin-D, norfloxacin and other NorA substrates in mycobacteria 23.
New Combinations with Efflux Pump Inhibitors: Change of current efflux pump inhibitors it has been noticed that it is not known whether the convergence of verapamil utilized as a part of in vitro studies is achievable in patients. Verapamil is likewise known to have negative cardiovascular symptoms. It is, in this manner, imperative to additionally research efflux pump inhibitors as a reasonable treatment choice by enhancing current efflux pump inhibitors and scanning for a new compound. One such illustration is nor-verapamil, a metabolite of verapamil that has lower Ca+2 channel blocking activity. Nor-verapamil showed an in distinguishable activity from verapamil for hindering macrophage induced drug resistance in a macrophage contamination model 24.
Additionally, newly research rivaled that display efflux pump inhibitor activity in mycobacteria. Farnesol (15-carbon isoprenoid segment) is a characteristic plant metabolite that represses oxidation-decrease activity and disturbs cellular film integrity by bringing about K+ leakage from the cytoplasm. In a chequerboard combination assay directed in M. smegmatis, the blend of farnesol and ethidium bromide at a concentration of 32mg/L {Fractional inhibitory concentration (FIC1/4 0.625); an index value used to evaluate the interaction of various drugs} diminished the MIC of ethidium bromide by 8-and 4-fold, separately, at 16mg/L (FIC1/4 0.375).
Moreover, collaboration was seen amongst farnesol and rifampicin. The potential clinical utilization of farnisol is highlighted by its medicinal strength and in addition its low lethality in people 25. Another compound showing efflux pump inhibitor action is a mammalian pump inhibitor, timcodar (in the past VX-853). An adjuvant impact was shown in synergized with antimicrobial drugs (rifampicin, bedaquiline and clofazimine) when M. tuberculosis was cultured in host macrophage. A similar efflux pump inhibitor in a blend with either rifampicin, bedaquiline or clofazimine brought about a ten times increment (IC50 of 1.9mg/L) in the development restraint of M. tuberculosis and the synergy combination was seen in a blend with rifampicin, moxifloxacin and imperatively, in a mouse model of contamination, timcodar treatment brought about 1.0 and 0.4 log10 reductions in bacterial burden when utilized as a part of the combination with rifampicin and isoniazid, separately. These process its guarantee as an adjuvant treatment 26.
CONCLUSION: The latest research has demonstrated that Multi drug resistance in M. tuberculin is related with the consecutive or inducible articulation of efflux frame works. The many sided quality of resistance mechanism, for example, those intervened by efflux pumps have permitted M. tuberculosis to develop such that currently conceivably potentially to most against tuberculosis drugs.
This highlights the requirement for the improvement of new treatment regimens. Such regimens could potentially incorporate the utilization of efflux pump inhibitors, in conjugation with the existing of new drugs, to help build the potency of current against tuberculosis drugs. Some encouraging in-vitro and in-vivo reports propose the significance of utilizing efflux pump inhibitors as aides to enhance TB chemotherapy. These efflux pump inhibitors (manufactured or got from plant or bacterial sources) target different classes of pumps and can be assembled in to a broad spectrum or specific inhibitors. Broad spectrum inhibitors are the perfect contender for adjuvant treatment therapy. However, these are hard to create and represent a serious risk of being more poisonous to human cells.
Specific inhibitors, for examples, inhibitors of cytochrome bcd are a great contender for diagnostic purposes. Despite the fact that, it is a potentially preferred standpoint to utilizing clinically affirmed efflux pump inhibitor in combination treatment therapy, it is basic to tailor the pharmacokinetics of the efflux pump inhibitor to the pharmacokinetics of the antibiotics with a specific end goal to upgrade combination of the multi drug. Promising advances have given new would like to the outline and adequacy of efflux pump inhibitor / antibiotic combination regimens, focusing on efflux pump activity to enhance tuberculosis treatment.
The design of efflux pump inhibitor analogues of known efflux pump inhibitors, for example, verapamil, has likewise been investigated as of late and turned out to be a useful optional route. These incorporate certain natural sources (e.g. plants) that can be misused for therapeutic purposes, as observed with berberine, piperine and reserpine. The inhibitory compounds appear to improve the action of existing against TB drugs, either through synergism or added substance impacts. This perception emphasise the requirement for more propelled reviews on this subject.
An extra captivating character for efflux pump inhibitors is their profound chance recurrence, making them stronger against M. tuberculosis at restoratively achievable focuses. Certain natural compound, for example, reserpine, piperine, and berberine may be exploited synergistically with current tuberculosis treatment regimens to enhance the therapeutic efficacy. Moreover, molecular docking investigations of well studied concentrated putative efflux pumps could advance our insight on the potential utilization of efflux pump inhibitors as aside to synergistically repurpose conventional against TB drugs. In gist, it is evident from the present review that utilization of efflux pump inhibitors may offer a successful methodology to upgrade the strength of the current and recently develop hostile to TB drugs.
ACKNOWLEDGEMENT: Gyanendra Singh is highly thankful to University Grant Commission, New Delhi for financial support through fellowship Pharmacy, Engineering Science and Technology.
CONFLICT OF INTEREST: The authors report no conflicts of interest.
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How to cite this article:
Singh G and Srivastava AK: Efflux pump inhibitors: Enhance therapy and cauterize Tuberculosis. Int J Pharm Sci Res 2017; 8(7): 2762-67.doi: 10.13040/IJPSR.0975-8232.8(7).2762-67.
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Article Information
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2762-2767
350
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English
IJPSR
Gyanendra Singh* and A. K. Srivastava
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, (Banaras Hindu University), Varanasi, Uttar Pradesh, India.
gsingh.rs.phe@itbhu.ac.in
21 January, 2017
20 June, 2017
21 June, 2017
10.13040/IJPSR.0975-8232.8(7).2762-67
01 July, 2017