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��ࡱ�>��	�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������[�	���bjbj����	4�ΐΐ�l�������������----�<-�.jUUUUU000t,v,v,v,v,v,v,$�0��3@�,��00���,UU�;.�'�'�'�@UUt,�'�t,�'�'D*�*U������ ]�-�&�\*`,Q.0�.d*,�3~'"�3�*�*�3�*�0,\��'2���000�,�,�'"000�.�������������������������������������������������������������������������3000000000�	�:	Activity of pomegranate against clinical isolates of Mycobacterium tuberculosis and �-Lactamase Producing Klebsiella pneumoniae
Diganta Dey 1,2, Ratnamala Ray 2, Banasri Hazra 1,*
1 Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
2 Department of Microbiology, Ashok Laboratory Clinical Testing Centre Private Limited, Kolkata 700068, India
*Corresponding author.
E-mail address: banasrihazra@yahoo.co.in (B. Hazra).

Abstract 
Considering the world-wide emergence of antimicrobial resistance, we have investigated therapeutic potential of pomegranate fruit and some of its polyphenolic ingredients, viz. caffeic acid, ellagic acid, epigallocatechin-3-gallate (EGCG) and quercetin. The edible as well as non-edible parts of pomegranate along with the constituent compounds were evaluated against clinical isolates of M. tuberculosis, extended-spectrum �-lactamase (ESBL) and KPC-type carbapenemase producing K. pneumoniae, and their representative ATCC strains.

Clinical isolates were characterized by routine laboratory method and therapeutic potential of the tested extracts and compounds were evaluated in terms of minimum bactericidal and bacteriostatic concentrations (MIC and MBC).

Pomegranate fruit peel extracts exhibited greater antitubercular activity (MIC 64 - 1024 �g/mL) than the lyophilised juice (MIC 256 - >1024 �g/mL). EGCG and quercetin exhibited higher antitubercular (MIC 32 - 256 �g/mL) and antibacterial (MIC 64 - 256 �g/mL) potency than caffeic acid and ellagic acid (MIC 64   512 �g/mL). Overall, the tested samples exhibited greater activity against M. tuberculosis as compared to the �-lactamase producing K. pneumoniae isolates. 

Thus, the antitubercular activity of pomegranate fruit extracts and pure constituents were reported for the first time against such a broad panel of M. tuberculosis and �-lactamase producing K. pneumoniae isolates. The catechins and flavonoids, like EGCG and quercetin, are found in many plant foods including pomegranate, and need to be investigated further for their prospective application against respiratory infections.

Keywords 
Pomegranate; Antitubercular; Antibacterial; Epigallocatechin-3-gallate; Quercetin; Extended-spectrum �-lactamase; Carbapenemase; Clinical isolates

Abbreviations
ATCC: American Type Culture Collection; ATD: Anti-tubercular drug; CLSI: Clinical and Laboratory Standards Institute; EGCG: epigallocatechin-3-gallate; ESBL: Extended-spectrum �-lactamase; FAS: Fatty acid synthase; HIV: Human immunodeficiency virus; KPC: Klebsiella  pneumoniae carbapenemase; LJ: L�wenstein�Jensen; MBC: Minimum bactericidal concentration; MDR-TB: Multi-drug resistant tuberculosis; MHA: Mueller Hinton agar; MHB: Mueller Hinton broth; MIC: Minimum inhibitory concentration; MTC: Mycobacterium tuberculosis complex; MTT: 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; PCR: Polymerase chain reaction; TB: Tuberculosis; WHO: World Health Organization; XDR-TB: Extensively drug resistant tuberculosis. 
Introduction
Pomegranate is the fruit of Punica granatum Linn. (Punicaceae), well known for its nutritious and medicinal value since antiquity. It is recommended for the treatment of parasitic diseases, aphthae, diarrhea and ulcers in Ayurvedic medicine, and regarded as anti-diabetic in the Unani system practiced in the Middle East and India [1]. Numerous studies on its antioxidant, anticarcinogenic, anti-inflammatory and antimicrobial properties were reported in the past decade [1-3]. Pomegranate juice and peel could provide protection against hepatotoxicity, methicillin-resistant Staphylococcus aureus, human immunodeficiency virus (HIV), genital herpes virus, tumour, and also exhibited estrogen-like activity, as well as hypolipidemic property [2]. Again, various extracts derived from pomegranate were shown to possess antimicrobial activity [1-3]. However, no significant study on its inhibitory activity against Mycobacterium tuberculosis has been reported so far, to the best of our knowledge. 
Mycobacterium tuberculosis is the causative agent of the contagious respiratory disease known as tuberculosis (TB). World Health Organization (WHO) estimated that ~9 million new infections and ~1.4 million TB deaths had occurred worldwide during past one year [4]. Thus, M. tuberculosis was responsible for more mortality than any single microbial species, and TB remains a global threat to health care systems even after 40 years of the introduction of antitubercular chemotherapy [5]. Currently, the emergence of multi-drug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB), in association with immuno-compromisation due to HIV, have aggravated the scenario which solicits an urgent need to develop new therapeutics to combat TB [6].
Again, Klebsiella pneumoniae, the most prevalent Gram-negative pathogen of Enterobacteriaceae family, is primarily responsible for the outbreaks of nosocomial infections in intensive care, burn, oncology and neonatal units [7]. A strong correlation between �-lactam antibiotics used against these diseases and resistance development due to the �-lactamases (the related inactivating enzymes) has been observed over the past half-century [8]. Then, the first report of plasmid-mediated extended-spectrum �-lactamases (ESBLs) capable of hydrolyzing third- and fourth-generation cephalosporins and monobactams was published in 1983 [9]. Moreover, ESBL-containing plasmids often carry resistance genes for other antibiotics, such as aminoglycosides and fluoroquinolones, also. Therefore, carbapenems were the treatment of choice for serious infections caused by ESBL-producers. However, in 1996, the first carbapenem resistant K. pneumoniae carbapenemase (KPC) -producing K. pneumoniae isolate was reported in Eastern USA. Since then, KPC-type carbapenemase producers had spread globally and are now endemic in US, Israel and Greece [10]. High mortality rate was documented (~30% � 50%) in KPC-type carbapenemase producing K. pneumoniae infections [7], as most of these isolates were resistant to extended-spectrum cephalosporins, co-trimoxazole, fluoroquinolones, and aminoglycosides, in addition to the carbapenem drugs [10]. A limited therapeutic option against the aforesaid isolates thus justifies the necessity for exploring the scope of alternative medicines. 
Presently, we have investigated the antitubercular and antibacterial activity of polar extracts (methanol and water) of the inedible part of pomegranate (peel) and the lyophilized juice. Additionally, some of its polyphenolic ingredients, viz. caffeic acid, ellagic acid, epigallocatechin-3-gallate (EGCG) and quercetin (Fig 1), which are well-known as the nutraceutical constituents of several dietary plants, have been investigated against drug resistant clinical isolates. To our knowledge, apart from the in vitro and in silico analysis of molecular interactions [11-16], no detailed work has been reported so far on the inhibitory activity of these selected compounds against Mycobacterium tuberculosis and �-lactamase producing Klebsiella pneumoniae isolates.

Materials and Methods 
Plant materials and test compounds
The non-edible pericarp of the ripe pomegranate (P. granatum) fruits, procured freshly from a local market, was separated from the arils, and dried under shade. The fresh arils were crushed to extract the juice of pomegranate fruit (15 mL) and freeze-dried in a lyophiliser (J; 7 g). A sample (10 g) of the pulverised pericarp was refluxed in methanol for 2 h, and the extract was filtered to remove the solvent under vacuum (M; 2.9 g). Similarly, another sample (10 g) of the pericarp was extracted by boiling in water and freeze-dried (W; 4.8 g). �J�, �M�, and �W� were dissolved in dimethyl sulphoxide (DMSO; Merck Mumbai, India) for preparing the test solutions. 
Four key chemical constituents of pomegranate fruit, viz. caffeic acid (1), ellagic Acid (2), epigallocatechin-3-gallate (3), and quercetin (4), were purchased from Sigma�Aldrich Co., MO, USA (Fig 1). 

Isolation and identification of Mycobacterium tuberculosis
Detection of mycobacteria in clinical specimen was performed through enrichment in Middlebrook 7H9 broth using BacT/ALERT 3D system (bioM�rieux, Inc., Durham, NC, USA) as described previously [6]. The culture broth from the BacT/ALERT MP bottle with positive growth of Mycobacterium was inoculated in L�wenstein�Jensen (LJ) slant (HiMedia, Mumbai), and the growth was identified by phenotypic tests and routine biochemical methods, using the kits procured from Himedia, Mumbai [6, 17]. Additionally, real-time DNA detection for genotypic confirmation of Mycobacterium tuberculosis complex (MTC) was accomplished by using artus� M. tuberculosis RG PCR kit and Rotor-Gene Q analyzer (QIAGEN, Hilden) [6]. 

Anti-tubercular drug (ATD) susceptibility
Susceptibility testing of nine M. tuberculosis isolates along with one American Type Culture Collection (ATCC) strain of M. tuberculosis (H37Ra) was carried out against first line (isoniazide, ethambutol, pyrazinamide, refampicin, streptomycin) and second line (kanamycin, amikacin, ethionamide, D-cycloserine, clarithromycin, p-amino salicylic acid, rifabutin) ATDs on drug-incorporated LJ slants (HiMedia, Mumbai), following LJ proportion method [5, 6, 17]. 

Antitubercular activity
The susceptibility of ten selected M. tuberculosis isolates against the three test extracts and four compounds was determined by tetrazolium microplate assay with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT; Sigma-Aldrich, MO, USA) following standard protocol [6]. The lowest concentration within the range of 1024   0.5 and 512   0.25 �g/mL, respectively, for the extracts and pure compounds, at which tubercular growth was inhibited, as indicated by the colour change of MTT, was noted as the minimum inhibitory concentration (MIC) of the tested antimycobacterial. To determine the minimum bactericidal concentration (MBC), a loop-full of culture from each well containing different dilutions of the tested antimycobacterials was streaked by a 4mm loop (HiMedia, Mumbai; calibrated to 0.01 mL) on solid LJ medium base containing glycerol (HiMedia, Mumbai). The lowest concentration of the tested compound that did not support the growth of visible mycobacterial colony on LJ medium was recorded as the MBC [6].

Isolation and characterization of Klebsiella pneumoniae isolates
A total of 20 bacteria, comprising of two ATCC strains and 18 pathogenic isolates of K. pneumoniae which were identified by routine phenotypic and biochemical methods [17], were screened for their ESBL and KPC-type carbapenemase producing capability by the following tests:

Double-disc synergy test
A third generation cephalosporin, viz., ceftazidime or cefotaxime (30 �g), and a disc of co-amoxiclav (20 �g amoxicillin/10 �g clavulanic acid) were placed 20 mm apart on Mueller Hinton agar (MHA) plate on which 0.5 McFarland of test organism was swabbed. In case of an ESBL producer strain, the zone diameter of cephalosporin disc was found to extend by e"5 mm towards the co-amoxiclav disc (Fig 2. A) [3, 17].

Phenotypic confirmatory test
Disc tests were performed for phenotypic confirmation of the presence of ESBLs in K. pneumoniae by using cefotaxime (30 �g) or ceftazidime discs (30 �g) with or without clavulanate (10 �g). In case of ESBL-producing bacteria, the zone diameter of cephalosporin/clavulanate disc was at least 5 mm greater than the zone for cephalosporin disc alone. K. pneumoniae ATCC 700603 was used as positive control for this test (Fig 2. B) [3, 18].

The modified Hodge test
0.5 McFarland standard suspension of E. coli ATCC 25922 in Mueller Hinton broth (MHB) was diluted to 1:10 in MHB and inoculated in MHA plates. An imipenem disc (10 �g) was placed at the centre of the plate. Then, 3 5 colonies of the test organism (grown separately in a blood agar plate) were picked with a 10 �L loop, and inoculated on the E. coli ATCC 25922 plate in a straight line from the edge of the disc. A characteristic clover leaf-like indentation, associated with the inoculation line of the KPC-type carbapenemase producer isolate, was observed at the periphery of the inhibition zone of E. coli ATCC 25922. K. pneumoniae ATCC BAA 1705 was used as positive control for this test (Fig 2. C) [3, 18].

Antibacterial drug susceptibility
Antibacterial susceptibility studies were carried out by Kirby and Bauer disk diffusion technique using commercially available antibiotic discs (HiMedia, Mumbai) and interpretation of inhibition zone data were done by according CLSI guidelines [3, 18].

Antibacterial activity
The broth micro-dilution assay was used for the determination MIC to find the lowest concentration within the range of 1024   0.5 �g/mL for three extracts and 512   0.25 �g/mL for four pure compounds against each of the selected K. pneumoniae (two ATCC strains and 18 clinical isolates) at which no growth was visible following the established procedure [3, 6, 18]. To determine MBC, a loop-full of culture was taken from each well containing different dilutions of the tested compounds, and inoculated by a 4mm loop (calibrated to 0.01 mL) on MHA plate. The lowest concentrations of the tested compounds that did not support the growth of visible bacterial colony were recorded as the MBC of the respective compounds [6].

Results
Antitubercular activity
The pomegranate fruit extracts, viz. J, M and W, along with the pure compounds (1 � 4) were evaluated for the antitubercular efficacy against one ATCC strain (H37Ra) and nine clinical isolates of M. tuberculosis, in terms of MIC and MBC (Table 1). M. tuberculosis isolates were collected from the pulmonary tuberculosis cases and their ATD resistance pattern was determined using LJ proportional method [17]. Among the selected tubercle bacilli, a single isolate (Mtb 10) originated from multi-drug resistant tuberculosis (MDR-TB) infection, and the other one (Mtb 5) from extensively drug resistant tuberculosis (XDR-TB). MDR-TB is caused by the strains of M. tuberculosis that are primarily resistant to isoniazid and rifampicin, while additional resistance to a fluoroquinolone (e.g. ciprofloxacin), as well as one second-line injectable agent (e.g. amikacin/ kanamycin), is considered as XDR-TB [4, 5]. 

Data in Table 1 showed that the methanol (M) and water (W) extracts of pomegranate fruit pericarp exhibited greater antitubercular activity (MIC 64 � 512, and 64 � 1024 �g/mL, respectively) than J, the lyophilised juice (MIC 256 � >1024 �g/mL). Among the pure constituents studied here, EGCG and quercetin exhibited higher potency, with the MIC 32 � 256 �g/mL, than caffeic and ellagic acid (MIC 128 � 512 and 64 � 512 �g/mL respectively). MIC of EGCG was found to be high (256 �g/mL) against isoniazid resistance isolates (Mtb 5, 8 and 10). Similarly, ciprofloxacin resistant isolates (Mtb 5 and 8) exhibited greater resistance against quercetin with MIC of 256 �g/mL. MBC/MIC ratio of the extracts and compounds against all tubercular isolates was found to be less than �32� (Table 1). 

Antibacterial activity
The antibacterial efficacy of pomegranate extracts and constituents (1 � 4) was evaluated against K. pneumoniae, selected in the context of ESBL- and KPC type carbapenemase production related to their multi-drug resistant phenotypes, through a extensive screening of available clinical specimens. Apart from the two ATCC strains, eighteen clinical isolates were obtained from different patients suffering from pulmonary infections, superficial wounds, bacteremia, urinary and enteric infections caused by multi-drug resistant K. pneumoniae (Table 2), and were tested for individual antibiotic resistance pattern following CLSI guidelines [18]. 

The results of antibacterial evaluation, expressed as MIC and MBC in Table 2, showed pomegranate extracts were less responsive (MIC 256 - >1024 �g/mL) than the pure compounds tested. EGCG and quercetin were found to be the most potent (MIC 64   256 �g/mL), while caffeic and ellagic acid were moderately effective (MIC 128   512 �g/mL) against the ESBL and KPC type carbapenemase producing K. pneumoniae isolates. However, the extracts as well as the pure constituents of pomegranate exhibited greater activity against M. tuberculosis (Table 1) as compared to the activity against �-lactamase producing K. pneumoniae isolates (Table 2). Here also the MBC/MIC ratio was observed to be less than �32�.  

Discussion
All parts of pomegranate fruit, including the highly nutritious juice of its aril, have been used in various traditional remedies against acidosis, dysentery, microbial infections, diarrhea, helminth infection, hemorrhage and respiratory pathologies around the world. Recently, many investigations on P. granatum fruit have been undertaken with a view to validating the age-old therapeutic application of this ancient plant for treatment of infectious diseases caused by virus, bacteria, fungi and parasites [1, 2]. However, to the best of our knowledge, no scientific details were available on the prospective inhibitory activity of pomegranate fruits against M. tuberculosis and �-lactamase producing K. pneumoniae, in particular. The present study clearly exhibited the positive response of both these organisms to the treatment with pomegranate fruit extracts. In an earlier study, we had indicated that pomegranate peel extracts, with a relative abundance of phenolic and flavonoid constituents, possess greater antibacterial efficacy than the potable juice [3]. Similarly, in the present investigation, tubercle bacilli showed lower MIC values (Table 1) for the peel extracts prepared with a polar solvent like methanol or water (MIC 64 �1024 �g/mL) in comparison to the juice (MIC 256 - >1024 �g/mL). However, the activity of the tested extracts were found to be comparatively weaker against the  ESBL and KPC-type carbapenemase producing K. pneumoniae isolates, as shown in Table 2 (MIC 256 - >1024 �g/mL). 
The antitubercular efficacy of pomegranate observed in this study prompted us to select a few polyphenolic ingredients of this fruit, like caffeic acid, ellagic acid, EGCG and quercetin, which are also constituents of green tea, broccoli, sweet potato, berries, grapes, etc. [19]. Many such flavonoids and phenolic acids are common antioxidant constituents of fruits like apple, grape, pear, cherry, and various berries, which contain up to 200 � 300 mg polyphenols per 100 g fresh weight [20]. EGCG is the major catechin abundant in green tea and several fruits including pomegranate. The results from Table 1 clearly confirmed the greater potency of EGCG and quercetin against M. tuberculosis and K. pneumoniae isolates (MIC 32 - 256 �g/mL) in comparison to caffeic acid and ellagic acid (MIC 64 � 512 �g/mL). Gradisar et al. (2007) had also reported the antimicrobial activity of catechins including EGCG against Gram-negative bacteria at relatively high concentrations due to the poor penetration in the bacterial outer membrane. They further concluded that the catechins inhibited bacterial DNA gyrase by binding to the ATP binding site of the gyrase B subunit. Considering the great health impact of tea-catechins, NMR and molecular docking experiments were also performed by Gradisar et al. (2007) to study the interaction of catechins with their molecular targets [12]. In fact, target enzymes of various metabolic pathways specific to the pathogens are being explored extensively considering the emerging threat of multidrug-resistant isolates, and fatty acid biosynthesis pathway is one of them. Some of the studies concluded that EGCG could inhibit the component(s) of fatty acid synthase (FAS) type II, which is a characteristic of both bacteria and mycobacteria [13, 14]. Since isoniazid, a front-line drug for treating TB, is also known to inhibit FAS type II in mycobacteria, this enzyme has been recognised as a good target for antitubercular agents [5]. It may be noted that, in the present study, isoniazid resistant isolates (Mtb 5, 8 and 10) exhibited a greater MIC (256 �g/mL) against EGCG (Table 1). This might be due to the mutation and/or over-expression of the target protein(s) caused by similar resistance mechanism induced by both isoniazid and EGCG [5].   
Again, quercetin, one of the most abundant natural flavonoids found in onion, tea, and apple, was also shown to interact with DNA gyrase in Escherichia coli [11]. Likewise, in silico analysis by Suriyanarayanan et al. (2013) indicated subunit B of DNA gyrase in M. smegmatis and M. tuberculosis (H37Ra) as a probable target for quercetin, which inhibited the bacilli at MIC of 100�g/ml, in vitro. So far, this was the only available report in the literature about assay of this flavonoid performed against M. tuberculosis (H37Ra) [15].  Our results showed similar activity not only on the same strain (MIC 64 �g/ml), but also on several clinical isolates of M. tuberculosis with tested drug-resistance profile (Table 1). Incidentally, resistance to fluoroquinolones in M. tuberculosis is commonly associated with mutations in the conserved quinolone resistance-determining region of gyrA and gyrB [5]. In the present study, we found that quercetin was less sensitive (MIC 256 �g/mL) in ciprofloxacin resistance tubercular isolates (Mtb 5 and 8) (Table 1), which implies similar mode of resistance mechanism operating against quercetin and ciprofloxacin. However, such correlation was not found in the case of antibacterial data, probably due to the role played by additional nonspecific resistance mechanisms in Gram- negative bacilli [19].
The other two polyphenols tested here, viz. caffeic acid and ellagic acid, exhibited moderate activity (MIC 64 � 512 �g/mL) against M. tuberculosis and K. pneumoniae isolates. Recently, Biswas et al. (2013) identified ellagic acid and two other compounds as prospective inhibitors of M. tuberculosis DNA primase by performing high throughput screening of 2560 small molecules [16]. In another study, caffeic acid was tested against three M. avium subsp. paratuberculosis strains, but it was not found to be j���			>	@	`	d	f	h	j	


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�CJOJQJaJh�X�hDT�CJOJQJaJh�X�h�CJOJQJaJ,active [21]. Actually, the previous investigations regarding antibacterial/antitubercular activity of aforesaid plant-derived polyphenols were mostly limited to target-specific molecular interactions [12-16]. However, the present study was conducted in a clinical scenario to address the non-specific resistance mechanisms as well, operating in parallel, which might compromise the efficacy of the applied antimicrobial compounds [5, 17]. Nevertheless, the ratios of MIC to MBC were found to be less than �32�, indicating bactericidal potency of the tested extracts of pomegranate fruit and its pure constituents against the selected isolates [22]. Furthermore, the majority of the tested isolates were obtained from respiratory specimens, which would validate the age-old therapeutic reputation of pomegranate traditionally prescribed to the patients suffering from respiratory infections.
In summary, extracts of pomegranate fruit and its pure constituents were shown to be active against Mycobacterium tuberculosis and �-lactamase producing Klebsiella pneumoniae isolates for the first time. The catechins and flavonoids, like EGCG and quercetin, found in many plant foods including pomegranate need to be investigated further for prospective application against respiratory infections.
Acknowledgements 
D.D. acknowledges technical and management support provided by Ashok Laboratory Clinical Testing Centre Private Limited, Kolkata. Research Scientist Grant from the University Grants Commission, New Delhi, acknowledged by B.H.

Declaration of Interest
The authors declare that they have no conflict of interest.

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