The discovery of antibiotics in the 20th Century marked a watershed in the treatment of infections. The ability to treat the serious infections of the pre-antibiotic era stimulated advances in medical fields and enlarged the scope of medical care. However, while a drastic change has taken place in the causes of fatal infections, they are still a major cause of death the world over (World Health Report 2003). "Relentless and Dizzying Rise of Antimicrobial Resistance" (Nordberg et al 2004) has contributed in a large measure to the persistence of infections as a major cause of morbidity and mortality. Therefore, medicinal plants after primary antibacterial screening have now been evaluated for their activity against various multidrug resistant bacteria. Plant extracts/phytocompounds exhibiting strong antibacterial activity may interact with antibiotics. The interactions may be synergistic, neutral or antagonistic. Synergy with antibiotic is expected to be useful in antibiotic therapy. Although investigations in this direction are in their infancy, a number of phytocompounds exhibiting synergistic interactions with antibiotics have been isolated and characterized.
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The need for new and effective/efficient antibacterial therapeutics and diagnostics is necessary to improve the protection against pathogenic bacteria. Although we have current treatments such as antibiotics, bacteria are gaining resistance to these therapeutics at an alarming rate. That is why new therapeutic and diagnostic treatments are necessary. The implementation of nanotechnologies and nanomaterials to create new antibacterial nanomedicines that increased effectiveness and efficiency
Nanoemulsions are a class of extremely small droplets that appear to be transparent or translucent. They are usually in the range 50 to 200 nm but much smaller than the range (from 1 to 100 Î¼m) for conventional emulsions .Nanoemulsions of phytocompounds have been known to have inhibitory and bactericidal effects. These emulsions were evaluated for their antimicrobial activities against different pathogenic organisms. Widespread clinical application of phytocompounds in diseases has been limited due to poor aqueous solubility, and consequently, minimal systemic bioavailability. Nanoparticle-based drug delivery approaches have the potential for rendering hydrophobic agents like curcumin dispersible in aqueous media, thus circumventing the pitfalls of poor solubility.
Since their discovery during the 20th century, antimicrobial agents (antibiotics and related medicinal drugs) have substantially reduced the threat posed by infectious diseases. Over the years, antimicrobials have saved the lives and eased the suffering of millions of people. By helping to bring many serious infectious diseases under control, these drugs have also contributed to the major gains in life expectancy experienced during the latter part of the last century.These gains are now seriously jeopardized by another recent development: the emergence and spread of microbes that are resistant to cheap and effective first-choice, or "first-line" drugs.Some important examples include penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, multi-resistant salmonellae, and multi-resistant Mycobacterium tuberculosis.
Antibiotic resistance is the biggest challenge to the medical profession in the treatment of infectious diseases. Resistance has been documented not only againt antibiotics of natural and semi-synthetic orgin,but also against purely synthetic compounds or those which do not even enter the cells. The wide range of occurrence of antibiotic resistance suggests that, in principle ,any organism could develop resistance to any antibiotic. Infections caused by resistant microbes fail to respond to treatment, resulting in prolonged illness and greater risk of death. Treatment failures also lead to longer periods of infectivity, which increase the numbers of infected people moving in the community and thus expose the general population to the risk of contracting a resistant strain of infection
Superbugs - New Strains of Antibiotic Resistant Bacteria
The newest antibiotic-resistant bacteria are described in the 11 August 2010 issue of The Lancet as Gram-negative, enteric (intestinal) superbugs from India, Pakistan and the U.K. These bacteria carry a beta-lactamase gene for making metallo-beta-lactamase (an enzyme) that breaks an important bond in certain antibiotics and inactivates those antibiotics. When this gene and its enzyme are active, multiple potentially-useful antibiotics are inactivated and made useless.
Plants have been an important source of medicine for thousands of years. Even today, the World Health Organization estimates that up to 80 percent of people still rely mainly on traditional remedies such as herbs for their medicines. Its civilization is very ancient and the country as a whole has long been known for its rich resources of medical plants. Today, Ayurvedic, Hoemoeo and Unani, physicians utilize numerous species of medicinal plants that found their way a long time ago into the Hindu Material Media.
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Microbial diseases rank as number one cause for almost half of the deaths in underdeveloped and tropical countries. An expansive range of plants belonging to an equally wide variety of plant families, have yielded products with antibacterial properties. Phenols and polyphenols, alkaloids and glycosides are the most common classes of phytochemicals that have exhibited promising activity against a wide range of bacterial species. Some volatile essential oils of commonly used culinary herbs and spices have also shown a high level of antibacterial activity.Many herbs actually help the growth of indigenous microflora that in turn combats with the pathogenic organisms and thus aid in prevention and control of infectious microorganisms.The findings have also confirmed that many Indian plants viz., black pepper, clove, garlic, neem, terminalia chebula, tulsi, and turmeric among others, possess significant antimicrobial activity.
Ethnomedicinal plants contribution in primary health care are well established. The uses of various medicinal plants in management of infectious diseases including bacterial are well known and validated in many cases. The antimicrobial activity of medicinal plants extracts or metabolites are comparable with antibiotic in several cases in vitro. The plant derived antibacterials are yet to be evaluated for their therapeutic efficacy. Development of multidrug resistance (MDR)in pathogenic bacteria has created immense clinical problem in the treatment of bacterial diseases which resulted in increase interest in plant antibacterial and antipathogenic compounds to combat resistance problem. Therefore, medicinal plants after primary antibacterial screening have now been evaluated for their activity against various multidrug resistant bacteria. It is interesting to observe that plants exhibiting broad spectrum antibacterial activity are effective almost equally both against drug resistant and drug sensitive bacteria. Antibacterial compounds identified have shown promising activity in vitro. However, efficacy of antibacterial compounds in vivo against bacterial infection, pharmacology, drug interactions and toxicity has to be evaluated. Similarly, plant derived products which can enhance the antibiotic activity, by their synergistic interaction or reversing drug resistance or decreasing virulence and pathogenicity are other alternative strategies to combat drug resistance problem.
Mechanism of action:
The mechanism of action by which the phytochemicals exert their antibacterial activity was determined, viz bacterial enzyme, sortase inhibitory effect, DNA replication and bacterial toxin and enzyme inhibitory action, and causing lysis of bacterial cells.
About 80,000 species of plants are utilized for treating various diseases in different systems of Indian medicine. Since 1990s there has been a growing shift in interest towards plants as significant sources for new pharmaceuticals. Many pharmaceutical companies show interest in plant-derived drugs mainly due to the current widespread belief that 'Green Medicine' is safe and more dependable than the costly synthetic drugs, which have adverse side effects. Hippocrates (in the late fifth century B.C.) mentioned 300-400 medicinal plants . In the first century A.D.,
Dioscorides wrote Demateria medica, a medicinal plant catalogue which became the prototype for modern pharmacopias.The Bible offers description of approx. 30 healing plants. The Mohammedan culture enriched the vegetable Materia medica, which was further improved by those in Greece, Arabia and Persia . The flora of India comprises about 45,000 of plants species, from unicellular blue green algae to flowering plants. Natural products and their derivatives represent more than 50% of all the drugs for the clinical use in the world. During the last 40 years, at least a dozen potential drugs have been derived from flowering plants.
It is estimated that there are 250,000 to 500,000 species of plants on earth. A relatively small percentage (1 to 10%) of these is used as foods by both humans and other animal species. It is possible that even more are used for medicinal purposes. Indeed The fall of ancient civilizations forestalled Western advances in the understanding of medicinal plants with much of the documentation of plant pharmaceuticals being destroyed or lost. During the dark ages, the Arab world continued to excavate their own older works and to build upon them. Of course .Asian cultures were also busy compling their own pharmacopoeia. In the west the Renaissance years saw a revival of ancient medicine, which was built largely on plant medicinal.
Major groups of antibacterial phytocompounds:
Although essential oil and its components and phenolics have been reported as important antimicrobial phytoconstituents other classes of compounds too have been found to show activity against microbes. Alkaloids and glycosides are such two classes that have number ofbiological activities and strong antibacterial potential too.Alkaloids have exhibited promising activity against a number of other bacterial strains.Similarly a few glycosides too have presented with antibacterial potency .Other classes of compounds exhibiting antimicrobial
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properties are amines ,amino acid (cystine) derivative,anionic components, aromatic acids,chromanone acids, fatty acids, germacranolide,
lactones, monocyclic diaryl ether, proteins, steroids etc.
Antimicrobial combinations are used most frequently to provide broad spectrum empiric coverage in the treatment of patients who are seriously ill and who may be septicemic combionations of antimicrobials are chosen because an identified pathogen is resistant to inhibition and / or killing by conventional doses of single antimicrobials but against which the combinations may exert the desired antimicrobial activity.The clinical outcome may depend on the effect of antimicrobial combinations against individual microorganisms.The antimicrobial combinations decreases the emergence of resistant strains and dose related toxicity.Another important use of antimicrobial combinations is in the treatment of documented or suspected mixed (polymicrobial) infections.
Antimicrobial combinations helps to achieve invitro activity and clinical efficacy against organisms resistant to inhibition or killing by nontoxic concentrations of single agents but certain combinations of agents may yield antagonistic effects.
Synergism:a positive interaction
The combined effect of the drugs being examined is significantly greater than the expected resuls.
Antagonism: a negative interaction
The combined effect of the drugs being examined is significantly less than the expected resuls.
SYNERGY OF HERBAL DRUGS WITH ANTIBACTERIAL AGENTS:
Plant extracts/phytocompounds exhibiting strong antibacterial activity may interact with antibiotics. The interactions may be synergistic, neutral or antagonistic. Synergy with antibiotic is expected to be useful in antibiotic therapy. Although investigations in this direction are in their infancy, a number of phytocompounds exhibiting synergistic interactions with antibiotics have been isolated and characterized. Combinational effect of protoanemonum isolated from Ranunculus bulbosus with 22 antibiotics was evaluated. In one combination, protoanemonum-cefamendole showed strong synergism against S. aureus .The synergistic activity was determined for two xanthones, Î±-mangostin and rubraxanthon isolated from Garcinia mangostana with antibiotics against MRSA strains . Similarly, retin isolated from Sophora japonica could be hydrolyzed to quercetin which showed synergistic and additive effects with various antibiotics . Interactions of active plant extracts with ampicillin, chloramphenicol and or tetracycline were determined in the synergism assay. Synergistic interactions were observed
between antibiotics and extracts from clove, jambolan, pomegranate and thyme against Pseudomonas aeruginosa and Klebsiella pneumonia. Synergistic interaction of ethanolic extracts of Indian medicinal plants with Î²-lactam antibiotics, aminoglycosides and synthetic fluroquinilone indicated the synergistic interaction with one or more antibiotics (tetracycline, ciprofloxacin and chloramphenicol) but least with Î²-lactam antibiotics against S. aureus and
Some of the future guidelines are suggested in this area of research are:
a) There are greater need to develop simple, economical multitargeted
approaches and methods to get novel and most effective combinations of
biological activities. Activity against MDR bacteria and antibiotic reversal,
plasmid elimination, virulence and pathogenicity reduction, inhibition of
bacterial cell to cell communications (quorum sensing) are the potential
b) Synergy with antibiotic and herb-drug interactions should be studied in order
to enhance the activity of older antibiotics and safe integration of herbal drug
with modern medicine.
c) Herbal preparation with known efficacy in traditional system of medicine
must be standardized and can be directly tested for clinical trials both in
animals and humans. However, isolated compounds with therapeutic
efficacy should be regulated and tested for its toxicity and efficacy similar to
that of modern medicines
The investigations targeted to solve the problem of antibiotic resistance has led to discovery of efflux pumps and Multi Drug Tesistance pumps (MDRs) and there are studies to indicate that several compounds present in plants having negligible or no antibacterial activity are capable of inhibiting the efflux pumps, thereby making the most resistance microorganisms susceptible to even those plant derived antibacterials, which otherwise show very poor or no activity in in-vitro. It is therefore essential to investigate further the presence of such compounds from plants that can hinder and destroy the MDRs, and potentiate the effect of antibiotics. This can be major breakthrough in the time when world is facing the threat of drug resistance. The success achived using medicinal plants and herbal formulations based on Ethnomedicinal and traditional use against a number of bacterial infections, therapeutically, raises optimism about the future of phyto-antibiotics.
In vitro evaluation of synergy
The accurate prediction of synergy between commercial drugs or between a drug and a natural product based upon the results of in vitro testing is very crucial.A number of methods are used to detect synergy.However, the checkerboard and time-kill curve methods are the two most widely used techniques and the former is a relatively easy test to perform (White et al., 1996).
The checker board method is the technique used most frequently to assess antimicrobial combinations in vitro.The concentrations tested for each antimicrobial typically range frm 4 to 5 dilutions below the MIC to twice the MIC using two fold dilutions of each antimicrobial.The inoculum of the bacterial suspension added to each tube should be approximately 2x105 CFU per ml.The checker board consists of columns in which each tube contains the same amount of the drug A being diluted along the x axis and rows in which each tube contains the same amount of drug B being diluted on the y axis .Each square in the checker board contains a unique combination of the two drugs being tested.
Analysis of the synergy data
In all the above methods the interaction between the two antimicrobial agents is estimated by calculating the fractional inhibitory concentration of the combination (FIC) index. The FIC of each drug is calculated by dividing the concentration of the compound present in that well in combination where complete inhibition of growth of the microorganism is observed by the MIC of that compound alone to inhibit the microorganism. The FIC of the combination is then the sum of these two individual FIC values. When the FIC index of the combination is equal to or less than 0.5, the combination is termed as synergistic; when FIC index falls between 0.5 and 4.0, it indicates 'no interaction' between the agents, and a value above four indicates antagonism between the two compounds (Odds, 2003).A convenient graphical way of representing the results of combination studies is by the use of an 'isobologram' introduced by Loewe and Muischnek (1926). It is independent of the mechanism of action, makes no
assumption about the behavior of each compound. So it is applicable to multiple component mixtures. Combinationof drugs X and Y that shows inhibition of the growth of the organism are represented in a graph using rectangular coordinates as (x,y) for the respective doses.
In this format, the dose of drug X alone as (a) and drug Y alone as (b) are represented along the axes as (a,0) and(0,b). The straight line connecting these points is called the 'line of additivity'. This line provides a convenient means for visually discriminating additive from nonadditive
interactions on the basis of whether or not the coordinate of the combination falls on (additive), below(superadditive) or above (subadditive) this line.
Synergistic interactions in other therapies
The successful use of combinations of plant extracts is not only observed in antiinfective therapy, but also seen in the treatment of several disorders including cancer,HIV, inflammatory, stress-induced insomnia, osteoarthritis and hypertension The recent trend has been the ''herbal shotgun'' method like Ayurveda, where multitargeted approach of the herbals and drugs is used
Pathogenic bacteria remain a major health concern, which are responsible for causing a large number of deaths and hospitalizations each year. The need for new and effective/efficient antibacterial therapeutics and diagnostics is necessary to maintain and improve the protection against pathogenic bacteria. Current methods of bacterial diagnostics are inefficient as they lack speed and ultra sensitivity and cannot be performed on site. This is where nanomedicine is playing a vital role. The implementation of nanotechnologies and nanomaterials
to create new antibacterial nanomedicines that increased effectiveness and efficiency.Nanome-dicine is defined as the monitoring, repair, construction and control of human biological systems at the molecular level, using engineered nanodevices and nanostructures. This is the field
of science and technology for diagnosing, treating and preventing disease and traumatic injury, of relieving pain, and of preserving and improving human health, using molecular tools and molecular knowledge of the human body. A range of new potential antibacterial therapeutics and
diagnostics which implements nanotechnology, most of which are in early stages of research but has already shown positive signs of application into nanomedical therapeutics and diagnostics. With the use of new novel materials and technologies it seems that we will be able to create new antibacterial therapeutics that are more effective in combination with rapid and ultra sensitive bacterial diagnostics, which will hopefully allow us to obtain further protection
against harmful bacteria.
LIMITATIONS OF NANOTECHNOLOGY
Nanomedicine, incarnation of the nanotechnology based concepts has the potential to fix innumerable problems especially in the field of medicine. Like any other application of scientific advancement,nanotechnology has its own limitations. The nano based application for the treatment of health aliments include development of nanomotors or nanorobots that function at cellular level which can lead to energy utilization at least 10 times the normal range, therefore creating an energy imbalance. Nanoparticles systems, comprised of multiple components which are less than 100 nm. At this scale there is an extremely large volume to surface ratio that can manifest profound effects on the interactions of nanoscale devices with the biological counterparts. Nanoparticles are known to show increased toxicity due to their increased surface area. Nanoparticles formulations prepared from copper, cobalt, titanium oxide and silicon oxide had an inflammatory and toxic side effect on cells.Engineering nanoparticles react with various components of immune system for instance, release of proinflammatory and inflammatory cytokines, inflammogenic effects of cobalt and nickel nanoparticles, stimulation of TNF alpha secretion from macrophages by hydroxyapatite crystals that can lead to activation of phagocytes, generation of allergic mechanisms by carbon nanoparticles. Thus,nanoparticles have immunomodulatory potential that stimulate or suppress immune system which are undesirable effects in human bodyEngineered nanoparticles are known to posses major genotoxic effects such as interaction with DNA and non DNA targets, their interaction with components associated with cell growth cycle such as centromeres, cytoskeleton, microtubules etc induce polyploidy and aneugenic events during cell division.Some of the other possible effects of nanoparticles include metal release, desorption of organic components, interaction with SH groups and Zn fingers of key proteins, saturation of metallothionein, changes in DNA methylation, secondary genotoxic effects through inflammation and activation of leukocytes apoptosis/ necrosis and inhibition of key receptors/enzymes.
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Class : Liliopsida
Subclass : Commelinids
Order : Zingiberales
Family : Zingiberaceae
Genus : Curcuma
Species : Curcuma longa
Tamil : Manjal
English : Turmeric
Sanskrit : Haldi,Haridra
Malayalam : Manjal
Biological source: Dried as well as fresh rhizomes of Curcuma longa
Î± and Î² pinene
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Order : Piperales
Family : Piperaceae
Genus : Piper
Species : Piper nigrum
Tamil : Marichamu
English : Black pepper
Sanskrit : Milagu
Malayalam : Kurumulaku
Dried unripe fruit of perennial climbing vine Piper nigram
MICRO ORGANISM PROFILE: Staphylococcus aureus
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The name 'Staphylococcus' comes from the Greek word staphyle meaning a bunch of grapes and kokkos, meaning berry, and that is what staph looks like a bunch of grapes or little round berries under the microscope. Staphylococcus aureus is a facultative anaerobic, Gram-positive usually unencapsulated coccus . Staphylococcus aureus forms a fairly large yellow colony on rich medium. The bacteria are catalase-positive and oxidase-negative. S. aureus can grow at a temperature range of 15 to 45 degrees and at NaCl concentrations as high as 15 percent. Nearly all strains of S. aureus produce the enzyme coagulase S. aureus should always be considered a potential pathogen.
S. aureus can cause a range of illnesses from minor skin infections, such as pimples, impetigo, boils (furuncles), cellulitis folliculitis, carbuncles, scalded skin syndrome, and abscesses, to life-threatening diseases such as pneumonia, meningitis, osteomyelitis, endocarditis, toxic shock syndrome (TSS), chest pain, bacteremia, and sepsis. Its incidence is from skin, soft tissue, respiratory, bone, joint, endovascular to wound infections.
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