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Current Pharmaceutical Design, 2016, 22, 1-10 1
REVIEW ARTICLE
1381-6128/16 $58.00+.00 © 2016 Bentham Science Publishers
Alkaloids: An Emerging Antibacterial Modality Against Methicillin Resistant Staphylococcus aureus
Aini Pervaiz
1, Ruqaiyah Khan
2, Firoz Anwar
3, Gohar Mushtaq
3, Mohammad A. Kamal
4,5,6and Haroon Khan
1*1Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, KPK, Pakistan; 2Siddhartha Institute of Pharmacy, Near I.T.
Park, Dehradun, 248001, Uttarakhand, India; 3Department of Biochemistry, King Abdulaziz University, Jeddah. Saudi Arabia; 4King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah; 21589, Saudi Arabia; 5Enzymoics; 6Novel Global Community Educational Foundation; 7Peterlee Place, Hebersham, NSW 2770, Austrália
A R T I C L E H I S T O R Y
Received: April 23, 2016 Accepted: June 25, 2016 DOI: 10.2174/1381612822666160627 125305
Abstract: Methicillin-Resistant Staphylococcus aureus (MRSA) is a Gram-positive bacte- rium which causes community and hospital-acquired infections. Synthetic drug/antibiotic treatment for MRSA-related infections is becoming less effective and natural products may be an emerging new alternative for future antibacterial drug development. Alkaloids are a class of natural compounds which are known for their phytochemistry and pharmacology.
This review focuses on 32 alkaloids isolated from various plants that showed marked anti- bacterial activity against MRSA by acting through different mechanisms such as inhibition of pyruvate kinase, Quorum quenching effect, alteration in efflux pump in MRSA and in- tercalating of bacterial DNA, to name just a few. In addition, the use of recent plant alka- loids against clinical isolates of MRSA has also been discussed.
Keywords: Alkaloids, MRSA, different susceptibility mechanisms.
1. INTRODUCTION
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most prevalent drug-resistant bacteria. Development of antibi- otic resistance in pathogenic microorganisms is an ongoing public health threat. In 2012, Staphylococcus aureus was a leading cause of hospital-acquired infections in the United States and MRSA alone caused 80,461 infections leading to 11,285 deaths [1]. A dis- tinct increase in microbial resistance against antibiotics was ob- served over the last forty years in both medical as well as livestock sector [2]. MRSA bacterium was first discovered in the United States in 1968. Research conducted in 9 countries in 1974 showed that 2% of the overall S. aureus infection cases are the result of MRSA. This figure rose to 22% in 1995 and 85% in 2008, and has continued rocketing ever since [3]. After 1975, only sporadic cases were reported in the following 25 years. Report from Malaysia suggests the prevalence of community-acquired MRSA as a great threat to the healthy individuals as well [4]. The 3% hike in the identification of CAMRSA isolates was observed in their four MOH hospitals [5]. Efforts to tackle MRSA infections had consis- tently drawn the developing countries into the great economic bur- den of millions of dollars in their search of new, sensitive and safe treatment. Today, even the most successful antibiotic, vancomycin, has been reported to lose its susceptibility against MRSA [6]. From 2005 onwards, significant attention was given to MRSA belonging to sequence type (ST) [7].
S. aureus is a major pathogen in both hospitals as well as the community, responsible for a wide range of infections from the uncomplicated skin and soft tissue infections to more serious ill- nesses like pneumonia, endocarditis, and sepsis. Particularly
*Address correspondence to this author at the Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan; Tel: +92-3469578740;
E-mail: [email protected]
worrisome are multidrug resistant strains such as MRSA that have created an urgent need for improvement in MRSA therapies.
Resistance can arise through spontaneous mutations or through the acquisition of resistance genes by horizontal transfer [8]. In S.
aureus, efflux mechanisms have been demonstrated being able to confer resistance to several antimicrobial agents, including cipro- floxacin, erythromycin, tetracycline and biocides, hence conferring multidrug resistance to this organism [9]. Biofilm development was supposed to be one of the defense mechanisms since bacteria em- bedded in biofilms are more difficult to eradicate than planktonic cells [10]. MRSA was initially isolated 50 years ago, only two years after the introduction of methicillin in clinical practice. One of the concerns with S. aureus is the current extent of the prevalence of MRSA due to which it has developed into a major global health issue owing to its pathogenic potential to cause bloodstream infec- tions, pneumonia as well as surgical site infections. Antibiotic resis- tance due to bacterial enzyme -lactamase is also the growing global health concern. Due to rampant antibiotic overuse, the en- zyme is evolving new resistance activities at an alarming rate. - lactamase confers resistance to penicillin and related antibiotics by hydrolyzing their conserved 4-atom -lactam moiety, thus destroy- ing their antibiotic activity [11]. Bacteria of all species depend on a cross-linked peptidoglycan layer, which preserves cell shape and rigidity. This peptidoglycan layer is primarily composed of alternat- ing (1, 4) linked monosaccharides, specifically N-acetylgluco- samine and N-acetylmuramic acid. The latter is modified by a pen- tapeptide that always ends with two D-alanine residues. Cross- linking of peptidoglycan units is catalyzed outside the cytoplasmic membrane by cell wall transpeptidase enzymes. In this cross- linking process, a peptide bond is formed between penultimate D- alanine on one chain and pimelic acid (in Gram-negative) or L- lysine (in Gram-positive) residue on the other chain. The terminal D-alanine is cleaved off after the linkage is formed with the penul- timate residue. Beta-lactam antibiotics effectively inhibit bacterial
Haroon Khan
transpeptidases, and hence they are often called penicillin-binding proteins (PBP). By inhibiting cell wall synthesis, the bacteria be- come highly susceptible to cell lysis. Beta-lactamase has, in fact, evolved from the functional domain of PBP through the acquisition of the new hydrolase activity to protect itself from beta-lactam anti- biotic, thus rendering them ineffective. The beta-lactamase enzyme family is broad and it is characterized by varying degrees of antibi- otic resistance activity [12].
Resistance of S. aureus to -lactam antibiotics is acquired by the exogenous mecA gene, which encodes a modified form of Peni- cillin Binding Protein 2A(PBP2A), that does not permit proper binding due to its deep integration within cell wall structure and its low affinity towards Penicillin and related compounds, thereby preventing the inhibition of cell wall synthesis that this class of antibiotics cause [13].
In this alarming condition of MRSA resistance to most of the available antibiotics, natural products may prove to be a useful alternative [14]. Alkaloids are the most widely explored class of natural compounds [15] in terms of both phytochemistry and phar- macology. In this review, we encounter various alkaloids that showed sensitivity against MRSA and could be the lead com- pound(s) of clinical utility, hence requiring proper exploration.
2. ALKALOIDS AS ANTIBACTERIAL AGENTS AGAINST MRSA
The increased prevalence of antibiotic-resistant bacteria due to the extensive use of antibiotics may render the current antimicrobial agents ineffective to control some complicated bacterial infections.
This led the attention of investigators to explore therapeutic proper- ties of plants and their chemical constituents, due to its growing popularity as a beneficial and economical alternative remedy in many diseases and infections around the world. Thus, investigation for the discovery of novel substances that are active against human pathogens is an urgent need [16]. Of the reported alkaloids, several showed activity against MRSA (Table 1). The quinolone alkaloid evocarpine was obtained from Fructus euodiae which possessed marked activity against MRSA [17]. Tomatidine, a steroidal alka- loid, was extracted from the tomato plant. Results revealed that it exhibited very good susceptibility against MRSA [18]. Cholido- nium majus (papaveraceae) led to the isolation of benzol[c]phenan- thridine type alkaloids, including 8-hydroxydihydrosanguinarine and 8-hydroxydihydrchelerythrine. These alkaloids possessed activ- ity against MRSA [19]. Clausenamallines G-K, carbazole alkaloids were obtained from Clausena wallichii. These alkaloids were very effective against MRSA PK1 [20]. Another quinolone alkaloid, 4- methoxy-N-methyl-2-2quinolone, was isolated from Zanthoxylum monophyllum and it also demonstrated strong inhibition against MRSA activity [21]. Harmandianamines A-C are carbazol alkaloids isolated from Clausena harmandiana. Harmandianamines pos- sessed effective activity against MRSA PK1 [22].
Glycosmis cochinchinensis contained various glycosmis indole alkaloids, which comprised of 1-hydroxy-3,4-dimethoxy-10- methylacridan-9-one, gama-fagarine, skimmianine, kokusaginine and intergriqinolone. When tested, these alkaloids also showed marked activity against MRSA [23]. Berberine, hydrastine and canadine were isolated from Hydrastis Canadensis. Hydrastine and canadine appear inactive against MRSA but with the addition of berberine, they produced quorum quenching effects against MRSA [24]. Stephania tetrandra contained bisbenzylisoquinolone alka- loids, tetrandrine and demethyltetrandine. These alkaloids showed potent activity against MRSA strains. When these alkaloids were used in combination with antibiotics like levofloxine, cefazoline, ampicillin, vancomycine and azithromycin, they produced synergis- tic-like therapeutic effects against MRSA activity [25]. Cienfue- gosia digitata possessed highly active alkaloids against MRSA because they had the ability to intercalate DNA, and destroy - lactamase [26]. The canthine-6-one type alkaloids (canthine-6-one,
8-hydroxy-canthine-6-one and 5-hydroxy-octadeca-6-(E)-8(Z)- dienioc acid) have been isolated from Allium plants and demon- strated strong susceptibility towards MRSA activity [27]. -pinene, 1,8-cineol and -terpineol alkaloids have been reported from Callis- temon rigidus with potent activity against MRSA [28]. Hylomecon hylomeconoides contain 6-methoxydihydrosanguinarine, 6- acetonylhydrosanguarine and dihydrosanguinarine. These com- pounds were very active against MRSA strains while 6-methoxy- dihydrosanguinarine caused the most dominant activity against MRSA [29]. Phytochemical analysis of Pterogyne nitens led to the isolation of two Guanidine alkaloids. These guanidine alkaloids were galegine and pterogynidine which possessed strong anti- MRSA activity. The antibacterial activity was attributed to the presence of side chain found in guanidine alkaloids [30]. 20-- dimethylamino-3--senecioylamine-16-hydro-pregn-5-5ene was pregnane alkaloid which was obtained from plant Pachysandra terminalis. It showed significant anti-MRSA activity by cytoplasm shrinkage of a bacterial cell that caused leakage of intracellular content, ultimately leading to cell death [31].
Schinus terebinthifolius belongs to the species of fungus and genera Alternaria, Colletotrichum, Diaporthe, Penicillium, and Xylaria. Upon screening, 64.7 % of the secondary metabolites were reported to produce antimicrobial compounds. (E)-2-Hexyl- cinnamaldehyde and pyrrolopyrazine alkaloids isolates produced compounds that inhibited the growth of MRSA (MIC of 18.52 g/mL) [32]
Colchicine is derived from the plant Colchicum autumnale L.
and has been explored for its antimicrobial activity against clinical isolates of MRSA. The inhibitory activity of colchicine derivative 2h with bis(2-methoxyethyl)amine substituent was obtained maxi- mum with the modification at C(10)-OCH3 position of C-ring [33].
Pyrrole-imidazole alkaloids citrinamines A-D and N- methylagelongine have been extracted from Agelas citrine and explored for their susceptibility against MRSA. This type of alka- loids is found to reverse the rendered resistance synergistically with oxacillin by inhibiting and dispersing the biofilm formation in S.
aureus. This markedly reduces the MIC to 4 fold [34]
Sanguinarine alkaloid has been reported to possess antibacterial activity, but it was found to possess synergistic susceptibility against the clinical isolates of MRSA when combined with EDTA and Streptomycin. The combination of an antibiotic and the alka- loid can re-sensitize the MRSA by targeting many mechanisms of resistance [35]. Ethonolic extractions of Hylomecon hylom- econoides by the researchers led to the isolation of very active compounds 6-methoxydihydrosanguinarine (6-MS), 6- acetonylhydrosanguinarine, and dihydrosanguinarine. When their inhibitory activity was explored against MRSA, they remarkably lowered the Minimum inhibitory concentrations (MICs) ranging from 1.95 to 250 g/mL of MRSA, thus making them potential natural alternatives to defend the alarming emergence of MRSA infections [29]. To further emphasize the important role of conven- tional plants, ethanolic extracts of Ocimum sanctum showed activ- ity against the MRSA strains of MIC ranged from 1.3 to 8.2 mg/mL, against MRSA bacteria. Thin-Layered-Chrometagraphy studies confirmed the presence of alkaloid in the extract suggesting its apparent potency against the resistant bacteria [36].
Bisindole alkaloids, i.e Deoxytopsentin and dibromodeoxy- topsentin, are naturally occurring sponge metabolites shown to be active against MRSA. Studies suggest that the antibacterial activity of those bisindole alkaloids is due to their inherent selective ability to target and inhibit Protein kinase enzyme [37].
Popular traditional medicines such as Vermonia blumeoides are already in use in Nigeria to treat infections. In search of the naturally effective drug against the emerging resistance of MRSA, Vermonia blumeoides has been investigated for its potency against MRSA. Its chloroform extract revealed the presence of an alkaloid,
Table 1. Structures of isolated alkaloids with prominent antibacterial activity against Methicillin-Resistant Staphylococcus aureus.
s.no Plant NAME Structure with Name Reference
1 Chelidonium majus Linn
N
O O
H3CO
OCH3 OH
CH3
8-hydroxydihydrochelerythrine
N
O O
H2CO
OCH2 OH
CH3
8-hydroxydihydrosanguinarine
[13]
2 Fructus euodiae
N R
O
CH3
Evocarpine
[11]
3 Tomato plant
NH O
RO
Tomatidine
[28]
4 Clausena wallichii Twings
NH H3CO
O
O
Clausenawalline C
NH H3CO
OH
OCH3 Clausenawalline D
[29]
(Table 1) Contd….
s.no Plant NAME Structure with Name Reference
NH H3CO
CHO
OH
NH OCH
HO
Clausenawalline E
NH H3CO
CHO
OH
NH OH H3CO2C
Clausenawalline F
5 Zanthoxylum mmo-
nophyllum N
O
4-methoxy-N-methyl-2quinonlone
[30]
6 Clausena
harmandiana Twigs
NH
O
OH O
Clausamine A
NH
O
OCH3 O
Clausamine B
[16]
(Table 1) Contd….
s.no Plant NAME Structure with Name Reference
7 Glycosmis
cochinchinensis
Twigs N
Me OMe MeO
OH O
1-hydroxy3,4-dimethoxy-10-methylacridan-9-one
N O
O
O
Gama-f agarine
N O
O
O O
Skimmianine
N O
O O
O
Kokusaginine
[17]
8 Hydrastis canadensis
H3CO N
O O
OCH3 H
Canadine
H3CO
N+
O O
OCH3 Berberine
[27]
(Table 1) Contd….
s.no Plant NAME Structure with Name Reference
N O
O
O H
OCH3
H3CO O
CH3 H
Beta-hydrastine 9 Stephania tetrandra
s.moore
N N
MeO
OCH3
OMe OMe
O O
Me H
H Me
Tetrandrine
[19]
10 Allium neoplatanum
N
N
O
Canthine-6-one
N N
O HO
8 Hydroxy canthine-6-one
O OH OH HO
HO
O
CH3 NH2
OH
5-Hyydroxy-octadeca-6-(E)-8(Z)-dienioc acid
[31]
11 Callistemon rigidus
Alpha-pinene O
CH3
H3C CH3
1,8 cineol
[22]
(Table 1) Contd….
s.no Plant NAME Structure with Name Reference
12 Hylomecon
hylomeconoides
N O
O
O O O
H3C H3C
6-methoxydihydrosanguinarine
[23]
13 Pterogyne nitens
NH NH2 NH
Galegine
HN HN HN
Pterogynidine
[24]
14 Topsentia
pachastrelloides
HN N
NH
O
NH Br
Spongotine A
HN N
H N
O
NH Br
OH
Bromotopsentin
HN N
H N
O
NH Br
Bromodeoxytopsentin
[26]
(Table 1) Contd….
s.no Plant NAME Structure with Name Reference
NH Br
HN
NH O
Br
cis-3,4-dihydrohamacanthin B
thus demonstrating antibacterial activity (20 mm) against MRSA exhibiting MIC of 1.25-2.5 mg/mL range [38].
For the strong implication and need of conventional therapy after antibiotic failure against MRSA, there was a tremendous stride to find newer molecules which tend to reduce the progression of bacterial infections and improve the patient life quality. With this urge, isolation of 6-methoxydihydrosanguinarine (6-MS), 6- acetonylhydrosanguinarine, and dihydrosanguinarine from Hy- lomecon hylomeconoides paved the way to regain drug sensitivity against MRSA. These alkaloids endeavour to successfully counter the desensitization of MRSA strains with MICs ranging from 1.95 to 250 ug/mL [29].
The Rutaceae plant has been the source of fluroquinolone and pyranoquinolone alkaloids, skimmianine, kokusaginine, and haplopine. These chemical constituents had been tested for their sensitivity against isolated strains of MRSA. They were found to inhibit these strains by binding to their DNA at a specific sequence and disrupting them and could be the feather cap in the utilization as anti-MRSA [39].
3. CLINICAL ISOLATES OF MRSA AND RECENT PLANT ALKALOIDS USE FOR THEIR TREATMENT:
The very first clinical isolate of MRSA was discovered in 1961, just one year after the introduction of methicillin in hospitals [40].
Nowadays, plants have become a useful and important source of antibacterial agents especially against the resistant strains of various species. These efforts are much under consideration by Guo-Ying Zuo, et al. [19]. This group of researchers have worked on clinical isolates of MRSA of sputum samples from patients of pneumonia, who were admitted to the intensive care units of the hospitals, and these researchers were able to prove that alkaloids from Berberis and Mahonia spp. (Berberidaceae), namely Berberine, were very effective in controlling the in vitro growth of at least ten isolates of MRSA when certain plant products were synergistically used along with other synthetic antibacterial compounds.
Hou-po is a traditional Chinese medicine containing various chemicals such as alkaloids and phenols which was tested for its anti-bacterial activity against clinical isolates of methicillin- resistant Staphylococcus aureus (MRSA) by Wei-Dong Pan, et al.
[41]. The results from this study suggest that the compounds found in this plant are able to work in vitro against the MRSA by partially altering the bacterial cell membrane penetration. Likewise, Wei- Dong Pan along with his co-workers was able to establish the anti- bacterial effects of Bisbenzylisoquinoline Alkaloids against at least ten clinical isolates of MRSA [42] when synergistically used with conventional antibacterial drugs. Extracts obtained from Lenzites quercina containing alkaloids from 14.4 to 20.7mg/g were tested for MRSA obtained from the Medical Microbiology Laboratory, Uni- versity College Hospital (UCH), Ibadan, Oyo State, and Ondo State Specialist Hospital, Akure, Ondo State. These alkaloids demon- strated antibacterial properties in six strains of MRSA [43]. Eleven strains of S. aureus which were methicillin resistant were tested for
MRSA antimicrobial activity of crude aqueous extract of T.
alternifolia. This plant contains the alkaloids along with other phyto-chemicals. The crux of this research indicates that the aque- ous extract of this plant possesses very good anti-bacterial proper- ties when compared to other solvent materials. Moreover, the aque- ous extract did not show any cytotoxic effects and was controlling the growth of MRSA and VRSA [44].
Fusidic acid (FA) and berberine chloride (BBR) were tested for in vitro synergistic effects on clinical isolates of methicillin- resistant Staphylococcus aureus (MRSA). Both of these two com- pounds were found to be very effective in controlling the growth of seven isolates out of thirty with marked reduction in biofilm forma- tion and destruction of mature biofilm in MRSA [45]. Antimicro- bial properties of R. and U. californica against MRSA have been shown by Carranza, et al. Their research established that chemicals from alkaloid groups, namely domesticine and nordomesticine, possess good anti-MRSA activities [46]. Similarly, Razmavar, et al.
have isolated novel chemicals from alkaloid family from the leaf extracts of Baeckea frutescens which are showing promising results against clinical strains of MRSA [47].
4. ANTIBACTERIAL MECHANISM(S) OF PLANT ALKA- LOIDS AGAINST MRSA
The bis-indol type of alkaloids has the ability to evoke antibac- terial effect through inhibition of pyruvate kinase. Pyruvate kinase is required to produce pyruvate for the Krebs cycle and inhibition of the enzyme would be expected to compromise ATP levels, resulting in disruption of the bacterial metabolism and thus ultimately lead- ing to bacterial cell death [48]. Berberine, hydrastine and candine are alkaloids obtained from Hydrastis candensis and they act by Quorum quenching effect. Quorum quenching effect is used to control the disease via quorum sensing system by triggering the pathogenic phenotype. It is believed that the effect was not to kill the bacteria but to shut down the expression of pathogen genes [49].
Reserpine (a phytoalkaloid) exhibits its antibacterial potential by inhibiting the efflux pump in MRSA [50].
Inhibition of MRSA activity of plant alkaloids could be attrib- uted to their ability to intercalate DNA. It has also been suggested that alkaloids components inhibit or destroy the action of - lactamase [48]. Analysis from scanning and transmission electron microscopy has indicated that the cytoplasm shrinkage of bacteria cells led to noticeable gaps between the cell membrane and the cell cytoplasm, and the severely damaged cell membrane resulted in leakage of intracellular content which ultimately caused the lethal effect of pregnane alkaloid on bacteria [31]. It is also believed that the quinolone alkaloids elicited inhibition of DNA gyrase and topoisomerase IV and could be the possible mechanism although it still needs experimental proof.
5. CONCLUSION
The above literature reveals that alkaloids are abundant in me- dicinal plants and a broad range of them possess strong sensitivity against MRSA. Of these alkaloids, the most effective are canthine-
6-one, pregnane, guanidine, bis-benzylisoquinoline, glycosmic indole, quinolone, carbazole, steroidal and benzol[c]phenanthridine type alkaloids. In the current scenario of MRSA resistance to most of the available antibiotics, further detailed studies on the efficacy, potency and safety of these alkaloids is required which could lead to the development of more effective therapeutic agents against MRSA.
LIST OF ABBREVIATIONS
MRSA = Methicillin-Resistant Staphylococcus aureus S. aureus = Staphylococcus aureus
MIC = Minimum Inhibitory Concentration CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of interest.
ACKNOWLEDGEMENTS Declared none.
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