Manuka and Myrtle Rust

Last week I attended a two day workshop organised by scientists at Plant and Food Research Ltd and Massey University in Palmerston North, to discuss a range of recent scientific and biosecurity developments, concerning Manuka (Leptospermum scoparium), an important plant in New Zealand’s natural environment and economy. As with the two day Hui on ‘Manuka and More’ in Ruatoria and Te Araroa in November last year, this was an excellent event in which more than 30 scientists working actively on Manuka research presented on a diverse range of subjects and discussed where there could be gaps in our knowledge or research needs for this plant. While Manuka Honey and essential oil are currently the main two medicinal products produced from Manuka, numerous other therapeutic applications and potential contributions to preserving our environment, are found within this plant.

Jacqui Horswell and colleagues from the Institute of Environmental Science and Research, have shown that Manuka and other myrtaceaeous plants seem to be capable of killing the faecal bacterial pathogen Enterobacter coli (E. coli), by enhancing the die-off of this and other pathogenic organisms that pass through their root systems. A field trial involving riparian planting of Manuka is just getting going, to see whether laboratory results extend to helping to reduce animal effluent flows into a polluted lake. A lake which was once pristine and a treasured swimming area, but in recent years has changed into a green and dirty waterway due largely to dairy industry runoff, has been selected for this trial.

Hayley Ridgway from Lincoln University presented some interesting findings concerning novel and potentially useful mycorrhizae (fungi) and endophytic bacteria associated with the roots of Manuka, some of which I wrote about in my previous blog. Inoculation of Manuka plants with different mycorrhizae causes significant alterations in their growth rates and essential oil composition, highlighting the complex inter-relationships between microbes associated with Manuka, and its production of phytochemicals including some with bioactive properties.

Other presentations were made on experiences to date involving plantations of Manuka which have been established at a number of North Island sites in recent years. Challenges include site access, weeds, pests, and the relative attractiveness of different genetic lines to bees. A comment made by one of the presenters that while humans have had multiple generations of experience with cultivation and enhancing performance characteristics of crops such as wheat and rice, our experience with Manuka plantations spans less than 10-15 years to date.

The hottest topic at the workshop, however, was the recent finding of isolated outbreaks of Myrtle Rust (Austropuccinia psidii) in New Zealand nursery and garden grown specimens of Manuka and the native tree, Ramarama (Lophomyrtus bullata). This pathogenic fungi originated from Brazil where it causes guava rust, but spread internationally into North America in the 1880’s, and was first reported in Australia in 2010.  Australia is home to around half of the world’s Myrtaceae (Myrtle family) plant species, including Eucalyptus (850 species), Melaleuca (176 species) and Callistemon species.

Outbreak of Myrtle rust has had a devastating effect on much of the east coast as well as other areas of Australia, where it has resulted in ecosystem collapse for certain plant species. To date it has only been found in isolated locations in Northland, Waikato, Bay of Plenty and Taranaki, although it is widespread on Raoul Island in the Kermadec group, about 1,100km to the north-east of New Zealand.

Myrtle rust spores can easily spread across large distances by wind, or via insects, birds, people, or machinery, and it is thought the fungus arrived in New Zealand carried by strong winds and significant weather events from Australia.

The Myrtle Rust Strategic Science Advisory Group is working hard to assess and try to ameliorate the widespread environmental, economic, social and cultural impacts this plant pathogen could have on New Zealand. Apart from Manuka and Ramarama, other indigenous Myrtaceae species such as Pohutakawa (Metrosideros spp) and Swamp Maire (Syzygium maire), are under risk. Priorities including acceleration of scientific research into the biology of the pandemic strain detected here, pathways of spread, surveillance, management, exploring plant susceptibility and resistance, and coordinating and communicating a management plan that has widespread engagement by communities, scientists, industry and Maori stakeholders and landowners, councils and government.

The Ministry for Primary Industries (MPI) and the Department of Conservation (DOC), with the help of local iwi, the nursery industry, and local authorities are running an operation to determine the scale of the situation and to try and contain and control myrtle rust in the areas it has been found. However, emergence of the infection and appearance of the distinctive yellow or brown leaf discolouration may not become fully apparent until the spring, and a better assessment of the number of infection sites and their extent, may not be possible until then.

The arrival of Myrtle Rust in New Zealand means that the task of collecting and storing seed of New Zealand indigenous Myrtaceae including Manuka, has now become urgent. The NZ Indigenous Flora Seed Bank (NZIFSB), a collaborative project between Massey University, AgResearch, Landcare and the Department of Conservation, with support from the NZ Plant Conservation Network and the Millennium Seedbank at Kew in the UK, was established in 2013. NZFISB has been doing some really valuable work to collect and store seeds aimed at preserving a wide range of biodiversity within New Zealand native plant species. More than 130 volunteer seed collectors have been trained to date, and plans are underway to extend this and the level of community participation, to try to better protect our native plants for generations to come.

Refs:

http://www.nzpcn.org.nz/page.aspx?conservation_seedbank

http://www.mpi.govt.nz/protection-and-response/responding/alerts/myrtle-rust/

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Antimicrobial Endophytes in Echinacea, Olive and Manuka

While plants are being extensively explored for new therapeutic properties and pharmacological activities, the communities of live fungi and bacteria known as endophytes that live between living plant cells, are also now being regarded as having many useful potential medicinal applications. Ironically, in recent years it is these microorganisms associated with plants rather than plants themselves, which seem to be receive much research interest.

Endophytes are microorganisms that live within a plant for at least part of their life cycles, without causing apparent disease or infections in the plant. Different endophytes seem to have affinities for particular plants, with which they have distinctive and cherished but complex interactions while each of them grows. They are for instance known to sometimes enhance host growth and nutrient gain, improve the plant’s ability to tolerate various types of stressors, and enhance the its resistance to insects and pests. The rrelationships that these bacteria and fungal communities have with their host plant varies from symbiotic to parasitic, to bordering on pathogenic.
Some very unusual and valuable bioactive substances are sometimes produced by these endophytes, such as alkaloids, phenolic acids, quinones, steroids, saponins, tannins, and terpenoids, and these are increasingly being recognized as sources of novel compounds which may help to maintain or solve not only the plant’s health challenges, but can also have applications in human and animal health problems.
Over the past few decades, some highly medicinal compounds produced by endophytic microbes lead to novel drug development. These include Taxol (paclitaxol), a complex diterpene alkaloid produced by the endophyte Metarhizium anisopliae found in the bark of the Pacific Yew (Taxus brevifolia) tree, and one of the most promising anticancer agents ever developed. Also streptomycin, an antibiotic produced from the bacterial endophyte Streptomyces.

Other endophytes possess antibacterial activities which may be useful in treating various infections, and in a world where antibiotic resistance is becoming a major public health threat, these are obviously of great interest. Exploring and bioprospecting these for potential antimicrobial compounds may well yield valuable new natural products or drugs to help in the fight against resistant organisms(1,2,3,4).

It now seems that bacterial communities colonizing Echinacea purpurea contribute to its well-known immune enhancing activity(5). American researchers have reported that Echinacea’s stimulating activity on monocytes (a type of white blood cell involved in engulfing and destroying harmful microbes), could be solely if not partially accounted for by the activities and prevalence of Proteobacteria, a family of bacteria found in the bacterial community associated with this medicinal plant.
A screen of 151 different endophytic bacteria isolated from three different compartments of Echinacea purpurea, revealed that several bacteria isolated from the roots are strong inhibitors of Burkholderia cepacia complex bacteria, a serious threat particularly in immune-compromised cystic fibrosis patients(6). One of these bacterial strains also showed antimicrobial effects against Acinetobacter baumannii, a pathogenic bacteria mainly associated with hospital-acquired infections, and Klebsiella pneumoniae, also increasingly incriminated in hospital infections(7). Interestingly, the type of bacteria and their antimicrobial effects varied considerably, according to which part of the plant (root, stem, leaves etc) they were associated with. This has resemblances to different plant parts of Echinacea having different phytochemical and thus pharmacological activities, such as Echinacea roots being richest in alkylamides and thus anti-inflammatory activities.

Endophytic fungi including Penicillium commune and Penicillium canescens (related to the Penicillium notatum mould from which the first antibiotic penicillin originated), have also been isolated from the leaves of olive (Olea europaea) trees, and several of these have also shown antibacterial as well as antifungal activities in recent work(8).

Finally, a rich endophyte community has recently been identified by Lincoln University researchers for the New Zealand native plant Manuka (Leptospermum scoparium). A total of 192 culturable bacteria were recovered from leaves, stems and roots, including some showing activity against the bacterial pathogen, Pseudomonas syringae pv. actinidiae(9), otherwise known by Kiwifruit growers as Psa. With Psa being a serious risk to the health of the Kiwifruit vine, it could be that these endophytic bacteria found within Manuka will make a useful contribution to ensuring the future health of the Kiwifruit industry.
While very few of all of the world’s plants have had their complete complement of endophytes studied, these are just three well established medicinal plants from which some highly active cohabitating bacteria and fungi have been sourced. Undoubtedly this area of research will receive much more attention due to growing concerns about antibiotic resistance, as there would seem to be a huge opportunity to find new and interesting endophytes among the wealth of different plants growing not only in soil, but also in waterways and oceans.
Refs:
1. Alvin A et al, Microbiol Res 2014; 169(7-8)L483-495.
2. Martinez-Klimova E et al, Biochem Pharmacol 2016; Oct 27.
3. Kealey C et al, Biotechnol Lett 2017; Mar 8 (epub ahead of print)
4. Tanwar A et al, Microbiol Path 2016;101:76-82
5. Haron MH et al, Planta Med 2016; 82(14):1258-1265.
6. Chiellini C et al, Microbiol Res 2017; 196:34-43.
7. Presta L et al, Res Microbiol 2017; 168(3):293-305.
8. Malhadas C et al, World J Microbiol Biotechnol 2017; 33(3):46.
9. Wicaksono WA et al, PLoS One 2016; 11(9):e0163717.

Manuka & More

I recently attended a very interesting Hui (Gathering) in Ruatoria and Te Araroa on New Zealand’s East Coast, entitled ‘Manuka and More’.  Around 15 researchers from Crown Research Institutes and industry representatives including myself gave talks on subjects related to the NZ native tree Manuka (Leptospermum scoparium), which grows prolifically around the coast, and provides nectar for honeybees which produce manuka honey.  Manuka honey is being increasingly recognised as a highly active natural product with benefits as an antimicrobial and wound healer, and global demand for it has soared in recent years. Similarly the volatile oil of manuka has antimicrobial and anti-inflammatory properties, and is increasingly sought after.

manuka-4
Studies into what makes manuka honey so special, and characterisation of its many different chemotypes and genotypes, has been a focus of much research in the past decade. To the East Coast locals, manuka was once regarded mainly as a scrub plant and nuisance that was cleared to make way for pastural farming of sheep and cattle, but with honey prices continuing to rise and there being little money now in wool, manuka is being allowed to re-establish itself in many areas. Additionally, a lot of effort is now going into planting nursery-raised seedlings bred from chemotypes thought to produce optimal quality and yields of honey and oil.

With the plantation model being in its relative infancy, research into the potential effects of planted manuka on the local pre-existing chemotypes, and whether the yield of honey or oil will in fact be as high as hoped from these cultivated plants, is an area for ongoing investigation.

A growing number of local East coast people and Maori-controlled enterprises are now getting into the honey producing business, and the number of hives in NZ has nearly doubled from around 350,000 to 700,000 over the past 5 years. The sustainability of this level of honey production is another area requiring research, particularly as bees only feed off manuka (and kanuka) nectar for around 6 weeks each season. Monitoring their activities and ensuring they have sufficient food for the remaining 46 weeks of the year, is important.

Of the various flowering plants NZ honey bees feed off, Willow trees (Salix species), are an important source of pollen and protein for bees to feed their brood in the spring time, thus helping them to expand their population and gain maximum strength before the start of the honey flow season. Around the East coast a large number of willows grow particularly along waterways and on erosion prone areas. While the biggest problems for young willows are grazing animals and pests such as possums, rabbits and hares, an emerging pest is also the giant willow aphid which first appeared in NZ in 2013. Apart from infesting willow trees, this can boost the populations of wasps that attack honey bees.

smaller-leptospermum-scoparium-flower-manuka-flower-julyWhile not pleasing to all, other flowering plants such as the invasive introduced gorse (Ulex europaeus), presently plays an important role as a food source for bees in some areas. However, we should be planting other native species such as Hoheria (Hoheria populnea),  Whauwhaupaku or Five Finger (Pseudopanax arboreus) and many others, to provide pollen and nectar as a replacement for that from this imported thorny plant.

Other research presented at the Hui related to the role that mycorrhizal fungi, which grow on the roots of most plants, may have in ensuring the health of the manuka shrub. Most plants co-exist with these fungi, which help them better absorb nutrients from the surrounding soil, and can also help with disease prevention. Also monitoring for potential disease or infestation threats to Manuka such as Myrtle rust, a serious fungal disease not present in New Zealand, but which can affect other plants in the myrtle (Myrtaceae) family.

Recent studies suggesting that manuka seems to be useful at soaking up excremental pollution, and thus may be an ideal tree to plant alongside waterways polluted by effluent runoff from our overly intensive dairy industry, point to yet another exciting development in our understanding about this amazing native plant.

Overall, the range and quality of the diverse areas of research being undertaken, was most encouraging. This combined with the hands-on experience and traditional knowledge of the local Ngati Porou people who are increasingly finding meaningful employment opportunities from manuka-based businesses, gives great encouragement to the future social, economic and environmental wellbeing, of this beautiful area of New Zealand.

Manuka Oil as an Alternative to Antibiotic Creams

New Zealand has a higher incidence of Staphylococcus aureus infections than anywhere else in the developed world, and there has been a significant increase in the number of infections over the past decade, with Māori and Pacific children particularly affected.

manuka-flower-macro

Over usage of an antibiotic is likely to have contributed to this paradoxical increase in serious skin infections, according to results from a Health Research Council funded study. This revealed an increase in the prevalence of resistance in Staphylococcus aureus from 17% in 1999, to 28% in 2013. Dr Deborah Williamson, the clinical microbiologist who lead the study, made the statement in a recent press release that “The increase that we’ve seen in the incidence of serious skin infections in New Zealand children has happened at the same time as an increase in the dispensing of topical fusidic acid to treat skin infections”(1).

Fusidic acid is an antibiotic derived from the fungus Fusidium coccineum and was first released for clinical use in the 1960’s. A 2% fusidic acid cream is currently recommended as a first-line treatment for serious skin infections such as impetigo (school sores), infection of the hair follicles and boils. Most of these are due to the bacteria Staphylococcus aureus, including the notorious methicillin resistant Staphylococcus aureus (MRSA). Like all antibiotics, drug resistance can develop, and this is invariably at a rate proportionate to the extent of usage.

In a paper published in the New Zealand Medical Journal last December, Dr Williamson reviewed the history and usage of topical antimicrobials in New Zealand (2).

This painted a somewhat alarming picture, and the fusidic acid story is an all too familiar one. Another topical antimicrobial agent widely used throughout the 1990s, mupirocin (Bactroban©), was for many years made available to purchase ‘over-the-counter’ (OTC). This led to high levels of use, and subsequent high rates of resistance, and by 2000, approximately 14% of S. aureus isolates displayed high-level resistance to mupirocin(3) . From April, 2000, regulatory changes lead to mupirocin being restricted again to ‘prescription only’, and the resulting decreased usage lead to a fall in the prevalence of high-level mupirocin resistance in S. aureus from 14.2% in 2000, to 8.3% in 2014 (4).

New Zealand is not alone in having a high rate of bacterial resistance to topical antimicrobials, and resistance to antibiotics poses a major global threat, according to a 2014 report by the World Health Organisation(5). Resistance is happening in every region of the world, and unless some major developments take place soon, humankind could be heading towards a time when once again, antibiotics cannot be relied upon to protect against simple infections including those that are risk factors associated with surgery. Development of strategies to mitigate further increases in antimicrobial resistance to topical treatments, is urgently required(6, 7).

Key to this, should be effective wound management. This should combine mechanical-chemical procedures such as debridement, antiseptics, and antimicrobial supportive compresses to help remove the biofilm (an association of microbes and slime which adheres to the surface of the wound, delaying granulation tissue formation and migration of epithelial cells).

Limitation of the level of usage of drug-based antimicrobials, or using two or more of them together rather than alone, and avoidance of topical antibiotic use in common conditions such as acne, are other ways to help reduce the likelihood of resistance(8).

Plants contain a large number of diverse chemicals (phytochemicals) which they produce as defence tools to enable them to survive in their particular environment, and some of these have potent antibacterial activities which can help us fight a wide range of common skin infections.

manuka-2The New Zealand native Manuka (Leptospermum scoparium) is one of these, and the ability of certain forms of Manuka Honey to act as potent healing agents for wounds and ulcers, is becoming increasingly recognised(8). Many clinical trials have now shown manuka honey dressings to have unique healing properties in chronic leg ulcers and other stubborn skin infections, and synergistic antimicrobial activities with various antibiotics, have recently been reported(10,11).

Manuka’s medicinal properties extend way beyond those of the honey that bees manufacture from its pollen, however, and other parts and extracts of this wonderful plant, have therapeutic activities. Manuka essential oil has also been shown to exhibit powerful antimicrobial properties, particularly against Staphylococcus aureus and other Gram positive bacteria, yeasts such as Candida albicans and fungi such as Trichophyton rubrum, responsible for athletes foot. Manuka oils which are rich in beta triketone compounds, appear to have the strongest antimicrobial activity.

The extent to which topical application of an extract of this plant can rival drug-based treatments at overcoming sores, was highlighted by a research project by two students at Whangaroa College in Northland recently. After hearing about a fellow student’s spider bite that wouldn’t heal until it was treated with a native plant preparation, the two students, Cheyenne Rush and Georgia Mills, decided to investigate the antibacterial properties of manuka essential oil and an extract of another native plant kawakawa (Macropiper excelsum).

Their experiment, which they entitled Te Rongoa Māori , involved collecting and growing colonies of bacteria, spreading these onto agar plates and applying a quarter of a teaspoon of each product to be tested. The relative rates of decline of the bacteria was recorded daily for 14 days, for the manuka oil and kawakawa extract preparations, in addition to the well known antiseptics Savlon® and Betadine®, which were applied to other agar plates as controls.

The results showed that manuka oil was the most powerful antibacterial, followed by Savlon® then Betadine®, with the Kawakawa leaf extract the least effective. Cheyenne and Georgia’s project thus showed that a simple, traditional plant preparation can be more effective than prominent antiseptic products in fighting wound colonising bacteria. It also won them a top prize at the recent Top Energy Far North Science and Technology Fair, which involved more than 150 participants from 10 schools in upper Northland(12).

Refs:

  1. Media Release from the Health Research Council, Soaring rate of skin infections linked to resistance.NZ Doctor, 20 September 2016.
  2. Williamson D et al, A bug in the ointment: topical antimicrobial usage and resistance in New Zealand. NZ Med J 2015; 128(1426):103-9.
  3. Upton A et al, Mupirocin and Staphylococcus aureus: a recent paradign of emerging antibiotic resistance. J Antimicrob Chemother. 2003; 51:613-617.
  4. Heffernan H et al, Demographics, antimicrobial susceptibility and molecular epidemiology of Staphyloccosu aureus in New Zealand, 2014. https://surv.esr.cri.nz/PDF_surveillance/Antimicrobial/Staph/2014Saureussurveyreport.pdf
  5. Antimicrobial Resistance: Global report on surveillance. World Health Organisation, who.int.ISBN 978 92 4 156474 8; (http://www.bbc.com/news/health-27204988).
  6. Williamson D et al, Missing in action: an antimicrobial resistance strategy for New Zealand. NZ Med J, 2015; 128(1427):65-67.
  7. Williamson DA, Hefferman H. The changing landscape of antimicrobial resistance in New Zealand. NZ Med J 2014; 127(1403):41-54.
  8. Walsh TR, The Lancet Infectious Diseases, 2016; 16(3): 23-33
  9. Carter DA, Front Microbiol 2016; 7:569
  10. Muller P et al, PLoS One 2013; 8(2):e57679
  11. Liu M et al, Front Microbiol 2015; 5:779.
  12. https://ssl-www.stuff.co.nz/auckland/local-news/northland/83909327/Manuka-proves-best-bacteria-fighter