tag:theconversation.com,2011:/us/topics/antifungal-chemicals-5667/articlesAntifungal chemicals – The Conversation2023-07-27T02:08:56Ztag:theconversation.com,2011:article/2010822023-07-27T02:08:56Z2023-07-27T02:08:56ZWhat is dandruff? How do I get rid of it? Why does it keep coming back?<figure><img src="https://images.theconversation.com/files/536006/original/file-20230706-25-n7njvh.jpg?ixlib=rb-1.1.0&rect=2%2C0%2C995%2C667&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/dander-that-causes-itching-scalp-373934782">Shutterstock</a></span></figcaption></figure><p>Dandruff can be dry, like snowflakes, or greasy, with yellow clumps. <a href="https://www.ncbi.nlm.nih.gov/books/NBK551707/">Up to half</a> of all adults have had this scalp condition at one point, so you’ll no doubt know about these skin flakes and the itchiness. </p>
<p>Dandruff can be <a href="https://onlinelibrary.wiley.com/doi/10.1111/j.1439-0507.2008.01624.x">embarrassing</a>. It can affect many aspects of people’s lives, such as how they socialise, how they style their hair, and what clothes they wear.</p>
<p>Dandruff is not a modern problem. In fact, it has been around for millennia and was <a href="https://pubmed.ncbi.nlm.nih.gov/2181905/">described</a> by Greek physicians. We don’t know for sure whether our ancestors were as bothered by it as much as we are today. But they were interested in what causes it.</p>
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<h2>What causes dandruff?</h2>
<p>Dandruff is mainly caused by the yeast <em><a href="https://www.cell.com/cell-host-microbe/pdf/S1931-3128(19)30106-4.pdf">Malassezia</a></em>. The yeast lives on most people’s skin, either on the surface or in the opening of the hair follicle, the structure that surrounds a hair’s root and strand.</p>
<p>The yeast feeds on sebum, the natural moisturiser secreted by your sebaceous glands to stop your skin drying out. These glands are attached to every hair follicle and the hair provides a dark, sheltered micro-environment ideal for the yeast to flourish.</p>
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<a href="https://images.theconversation.com/files/536003/original/file-20230706-22-6t0yr8.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram of skin cross-section showing hair follicle and other skin structures" src="https://images.theconversation.com/files/536003/original/file-20230706-22-6t0yr8.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/536003/original/file-20230706-22-6t0yr8.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=520&fit=crop&dpr=1 600w, https://images.theconversation.com/files/536003/original/file-20230706-22-6t0yr8.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=520&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/536003/original/file-20230706-22-6t0yr8.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=520&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/536003/original/file-20230706-22-6t0yr8.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=653&fit=crop&dpr=1 754w, https://images.theconversation.com/files/536003/original/file-20230706-22-6t0yr8.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=653&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/536003/original/file-20230706-22-6t0yr8.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=653&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">The yeast that causes dandruff lives on the skin surface and in the opening of the hair follicle.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/medical-education-chart-biology-hair-diagram-645657787">Shutterstock</a></span>
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<p>As the yeast grows, it releases molecules that irritate the skin and disrupts how the skin normally renews itself. This causes the cells to cluster together, appearing as white flakes. When there is excess sebum, this can mix with the cells and cause the dandruff to appear <a href="https://www.headandshoulders.co.in/en-in/healthy-hair-and-scalp/dandruff/yellow-dandruff">yellow</a>.</p>
<p>The link between dandruff and yeast was made nearly 150 years ago. The person who first identified and described this yeast <a href="https://www.cell.com/cell-host-microbe/pdf/S1931-3128(19)30106-4.pdf">in 1874</a> was Louis-Charles Malassez (the yeast’s namesake).</p>
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<h2>Why do I have dandruff?</h2>
<p>As <em>Malassezia</em> is found on most people, why do some people get dandruff and others don’t? This depends on a range of factors.</p>
<p>These include the quality of your skin barrier. This may mean yeast can penetrate deeper if the skin is damaged in some way, for example, if it’s sunburnt. Other factors include your immunity, and external factors, such as which hair-care products you use.</p>
<p>How <em>Malassezia</em> grows also depends on the <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864613/">balance</a> of other microorganisms that live on your skin, such as bacteria.</p>
<h2>How do I get rid of dandruff?</h2>
<p>Dandruff is mostly treated with <a href="https://www.sciencedirect.com/science/article/abs/pii/S0939641123000292?via%3Dihub">anti-fungal</a> shampoos and scalp treatments to dampen down growth of <em>Malassezia</em>. The shampoos most commonly contain the anti-fungal agent <a href="https://pubmed.ncbi.nlm.nih.gov/34575891/">zinc pyrithione</a> (ZnPT for short). Other common anti-fungals in shampoos include selenium sulfide, ketoconazole and coal tar. </p>
<p>You can also treat dandruff with scalp masks and scrubs that help restore the scalp barrier, by reducing inflammation and irritation. But as these may not have any anti-fungal action, your dandruff is likely to return.</p>
<p>Home remedies <a href="https://www.healthline.com/nutrition/ways-to-treat-dandruff#7.-Omega-3s">include</a> tea tree oil, coconut or other oils, and honey. There is some evidence to support their use, mostly from <a href="https://pubmed.ncbi.nlm.nih.gov/35642120/">studies</a> that show extracts from botanical ingredients can reduce growth of the yeast in the lab. But there is great variation in the quality and composition of these ingredients.</p>
<p>There is also the risk of making the problem worse by providing more oils that the yeast will enjoy, causing more imbalance to the scalp micro-organisms and leading to more irritation.</p>
<p>So it’s best to stick with commercial products.</p>
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<h2>Why does my dandruff come back?</h2>
<p>Your dandruff is likely to return unless the active ingredients in your shampoo can reach the right spot, at the right concentration, for the right amount of time needed to kill the yeast. </p>
<p>Our <a href="https://pubmed.ncbi.nlm.nih.gov/36842718/">research</a> focussing on zinc pyrithione-based products showed these shampoos reached the skin surface. But they less-reliably ended up in the harder-to-reach hair follicles.</p>
<p>We found the zinc pythione seemed <a href="https://pubmed.ncbi.nlm.nih.gov/35631659/">to target</a> the top of the follicles rather than deep into the follicles. </p>
<p>So this may explain why dandruff keeps on coming back. Your shampoo’s active ingredient may not reach the yeast that causes your dandruff.</p>
<p>We don’t yet know how we can encourage existing formulations to penetrate deeper into the follicles.</p>
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<h2>What about future treatments?</h2>
<p>We’ll likely see new formulations of dandruff shampoos and scalp treatments that better deliver the active ingredient to where it’s needed – deeper into the hair follicles.</p>
<p>We can also expect new active ingredients, such as <a href="https://pubmed.ncbi.nlm.nih.gov/28766952/">carbonic anhydrase</a> enzymes. These might target how the yeast grows in a different way to current active ingredients.</p>
<p>We are also beginning to see the development of creams and lotions that aim to boost the health balance of flora of the skin, much like we see with similar products for the gut. These include pre-biotics (supplements or food for skin flora) or pro-biotics (products that contain skin flora). However we have <a href="https://www.mdpi.com/2079-9284/8/3/90/htm">much to learn</a> about these types of formulations.</p>
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<h2>In a nutshell</h2>
<p>Dandruff is annoying, treatment helps, but you may need to repeat it. Hopefully, we can develop improved shampoos that better deliver the active ingredient to where it’s needed.</p>
<p>But we need to strike a balance. We don’t want to eliminate all micro-organisms from our skin.</p>
<p>These are important for our immunity, including preventing more disease-causing microbes (pathogens) from moving in. They also help the skin produce antimicrobial peptides (short proteins) that protect us from pathogens.</p>
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<img src="https://counter.theconversation.com/content/201082/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sean Mangion is also a medical student at The University of Sydney. </span></em></p><p class="fine-print"><em><span>Lorraine Mackenzie does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>We’ve known about dandruff for thousands of years. Here’s how to get rid of yours.Lorraine Mackenzie, Associate Professor, Clinical and Health Sciences, University of South AustraliaSean Mangion, PhD Candidate, University of South AustraliaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2092712023-07-26T11:09:48Z2023-07-26T11:09:48ZAustralian ant honey inhibits tough pathogens, new research shows<figure><img src="https://images.theconversation.com/files/539207/original/file-20230725-19-ukl2g.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C4031%2C3024&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Danny Ulrich and Andrew Dong</span>, <span class="license">Author provided</span></span></figcaption></figure><p>The medicinal value and potent antimicrobial activity of <a href="https://theconversation.com/science-or-snake-oil-is-manuka-honey-really-a-superfood-for-treating-colds-allergies-and-infections-78400">honey</a> has been a topic of considerable interest in recent years, particularly in light of the alarming rise in antibiotic resistance. </p>
<p>While most honey comes from honey bees (<em>Apis mellifera</em>), <a href="https://theconversation.com/wasps-aphids-and-ants-the-other-honey-makers-102838">other insects</a> such as stingless bees, wasps and even ants can produce honey-like products from plant nectar. </p>
<p>One of these insects is the honeypot ant <em>Camponotus inflatus</em>, found throughout the central desert region of Australia. We set out to determine whether its honey might be medically useful.</p>
<p>Our results, <a href="https://doi.org/10.7717/peerj.15645">published in PeerJ</a>, show the honey has powerful anti-microbial effects, particularly against certain heat-tolerant yeasts and moulds which resist most current antifungal drugs.</p>
<h2>Pots of gold</h2>
<p>Honeypot ants are social ant species that develop large nests in the soil. Within these colonies, certain worker ants known as “repletes” serve as living food stores. </p>
<p>The repletes are fed by other members of the colony, who forage for nectar and honeydew in the environment. The repletes accumulate a golden honey-like substance in their flexible abdomens. </p>
<p>The repletes become so engorged with honey they are rendered almost immobile. They hang together from the ceiling of the nest, forming a sort of ant pantry. </p>
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<img alt="" src="https://images.theconversation.com/files/539249/original/file-20230725-25-6avf8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/539249/original/file-20230725-25-6avf8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/539249/original/file-20230725-25-6avf8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/539249/original/file-20230725-25-6avf8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/539249/original/file-20230725-25-6avf8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/539249/original/file-20230725-25-6avf8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/539249/original/file-20230725-25-6avf8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Honeypot ant ‘repletes’ store honey for the nest.</span>
<span class="attribution"><span class="source">Andrew Dong</span>, <span class="license">Author provided</span></span>
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<p>In times of need, other worker ants visit the repletes and stroke their antennae. The repletes cough up some honey in response, and the other workers then distribute it throughout the colony.</p>
<p>Most honeypot ants live in very dry environments. Their unusual lifestyle has been so successful it has <a href="https://www.tandfonline.com/doi/abs/10.1080/03949370.1991.10721919">evolved multiple times</a>.</p>
<h2>Honeypot ants in First Nations culture</h2>
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<a href="https://images.theconversation.com/files/539244/original/file-20230725-28-emh9ho.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/539244/original/file-20230725-28-emh9ho.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/539244/original/file-20230725-28-emh9ho.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=645&fit=crop&dpr=1 600w, https://images.theconversation.com/files/539244/original/file-20230725-28-emh9ho.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=645&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/539244/original/file-20230725-28-emh9ho.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=645&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/539244/original/file-20230725-28-emh9ho.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=811&fit=crop&dpr=1 754w, https://images.theconversation.com/files/539244/original/file-20230725-28-emh9ho.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=811&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/539244/original/file-20230725-28-emh9ho.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=811&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Digging for honeypot ants.</span>
<span class="attribution"><span class="source">Danny Ulrich</span>, <span class="license">Author provided</span></span>
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<p>In Australia, <em>Camponotus inflatus</em> is found throughout the central desert region and holds cultural and nutritional significance to local Indigenous people. </p>
<p>Danny Ulrich of the Tjupan language group, operator of <a href="https://goldfieldshoneyanttours.com.au/">Goldfields Honey Ant Tours</a> in Kalgoorlie, Western Australia, says</p>
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<p>For our people, honey ants are more than just a food source. Digging for them is a very enjoyable way of life. It’s a way of bringing the family together, to connect with each other and nature. </p>
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<p>There are also reports of traditional use of honeypot ant honey for treating ailments like colds and sore throats, and possibly as a topical ointment to help keep infections at bay, suggesting potential antimicrobial properties.</p>
<h2>Not your usual honey activity</h2>
<p>To investigate further, we obtained honeypot ant repletes from Goldfields Honey Ant Tours, collected and pooled the honey from the ants and tested its ability to inhibit various pathogenic bacteria, yeasts and moulds. </p>
<p>We compared this to two well-studied bee honeys with anti-microbial properties: manuka honey from New Zealand, and jarrah honey from Western Australia. </p>
<p>Our <a href="https://doi.org/10.7717/peerj.15645">results</a> revealed striking differences between the honeypot ant honey and the bee honeys. </p>
<p>Both bee honeys showed broad activity and were able to inhibit every pathogen tested at similar levels. However, the honeypot ant honey showed remarkable potency against certain microbes, but little against others.</p>
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Read more:
<a href="https://theconversation.com/science-or-snake-oil-is-manuka-honey-really-a-superfood-for-treating-colds-allergies-and-infections-78400">Science or Snake Oil: is manuka honey really a 'superfood' for treating colds, allergies and infections?</a>
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<p>Important factors that contribute to the <a href="https://www.sciencedirect.com/science/article/abs/pii/S0023643820313682">antimicrobial power</a> of bee honey are its high sugar and low water content, which sucks the water out of microbial invaders.</p>
<p>We found honeypot ant honey to have a much higher moisture content than the bee honeys, however, putting it in a range that could support the growth of some microorganisms. </p>
<p>Most bee honeys also contain enzymes that produce hydrogen peroxide, a known antimicrobial compound. However, honeypot ant honey retained most of its activity even after we removed all the hydrogen peroxide. </p>
<p>Finally, some honeys contain antimicrobial proteins and peptides that are derived from the honey bee. These can be destroyed by heat, and when we heated the honeypot ant honey to 90°C for 10 minutes it lost most of its antimicrobial activity. </p>
<p>We therefore think this unique antimicrobial activity is likely due to proteins or peptides, and these are probably derived from the honeypot ant.</p>
<h2>Evolution of antimicrobial activity in the insect world</h2>
<p>In the natural environment, animals, plants, and the products they make are exposed to a huge range of microorganisms looking for their next meal. Sweet, nutritious honey is an enticing food source for these microbial scavengers and must be vigorously protected, both to prevent its spoilage and to stop invasion of the hive or nest by rapidly growing moulds. </p>
<p>Intriguingly, we found honeypot ant honey was particularly effective against some pathogens we consider to be quite “tough”. These pathogens are well adapted to living in soils and dry conditions, and can also cause very serious infections in people with severely weakened immune systems. </p>
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Read more:
<a href="https://theconversation.com/wasps-aphids-and-ants-the-other-honey-makers-102838">Wasps, aphids and ants: the other honey makers</a>
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<p>In particular, the ant honey was able to inhibit heat-tolerant yeasts and moulds that are likely to be present in the honey ant nest and surrounding environment. Importantly, these can be very difficult to kill with most currently available <a href="https://www.mdpi.com/2218-1989/10/3/106">antifungal drugs</a>.</p>
<p>We suggest the evolutionary pressure imposed by these soil microorganisms has resulted in the potent, selective antimicrobial activity of honeypot ant honey.</p>
<h2>Science catches up with Indigenous knowledge</h2>
<p>Our results clearly support the medicinal use of honeypot ant honey by Australian Indigenous communities and provide a new understanding of the intricate relationship between honeypot ants, their environment, and the remarkable antimicrobial activity exhibited by their honey. </p>
<p>Due to the cultural significance of the ants, and challenges with rearing them at a commercial scale, it is not feasible to domesticate honeypot ants for honey production. </p>
<p>However, honeypot ant honey may provide valuable insights for the development of useful new antimicrobial peptides. These may help expand our arsenal of effective antibacterial and antifungal treatments, which are increasingly needed to combat emerging challenges in healthcare.</p><img src="https://counter.theconversation.com/content/209271/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Dee Carter has received funding to support work on honey bee honey from The Rural Industries Research and Development Corporation, AgriFutures, the Australian Research Council (Linkage program), and the NSW Government under the Bushfire Industry Recovery Package.</span></em></p><p class="fine-print"><em><span>Danny Ulrich is the operator of Goldfields Honey Ant Tours.</span></em></p><p class="fine-print"><em><span>Kenya Fernandes conducts research on honey bees and medicinal honey supported by the NSW Government under the Bushfire Industry Recovery Package.</span></em></p><p class="fine-print"><em><span>Nural Cokcetin has received funding to support research on honey bees and medicinal honey from AgriFutures Australia and the NSW Government under the Bushfire Industry Recovery Package. She is a member of the NSW Apiarists' Association. </span></em></p><p class="fine-print"><em><span>Andrew Dong does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Experiments show honey from Australian desert ants has potent antimicrobial power.Dee Carter, Professor of Microbiology, University of SydneyAndrew Dong, Research Affiliate, Microbiology, University of SydneyDanny Ulrich, Operator, Goldfields Honey Ant Tours, Indigenous KnowledgeKenya Fernandes, Postdoctoral Researcher, University of SydneyNural Cokcetin, Research scientist, University of SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2034952023-05-03T12:10:09Z2023-05-03T12:10:09ZHow do ‘Candida auris’ and other fungi develop drug resistance? A microbiologist explains<figure><img src="https://images.theconversation.com/files/523473/original/file-20230428-18-9slhum.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2073%2C1368&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Candidiasis is a severe fungal infection that can spread easily in medical facilities.</span> <span class="attribution"><a class="source" href="https://flic.kr/p/8ysD2e">Atlas of Pulmonary Pathology/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>One of the scariest things you can be told when at a doctor’s office is “You have an antimicrobial-resistant infection.” That means the bacteria or fungus making you sick can’t be easily killed with common antibiotics or antifungals, making treatment more challenging. You might have to take a combination of drugs for weeks to overcome the infection, which could result in more severe side effects.</p>
<p>Unfortunately, this diagnosis is <a href="https://www.who.int/publications/i/item/9789240062702">becoming more common around the world</a>.</p>
<p>The yeast <em><a href="https://doi.org/10.1128/jcm.01588-17">Candida auris</a></em> has recently emerged as a potentially dangerous fungal infection for hospital patients and nursing home residents. First <a href="https://doi.org/10.3947%2Fic.2022.0008">discovered in the late 2000s</a>, <em>Candida auris</em> has very quickly become a <a href="https://doi.org/10.3390/microorganisms9040807">major health challenge</a> due to its ease of spread and ability to resist common antifungal drugs.</p>
<p>How did this fungus become so strong, and what can researchers and physicians do to combat it? </p>
<p><a href="https://scholar.google.com/citations?user=U69z9VsAAAAJ&hl=en&oi=ao">I am a microbiologist</a> researching new ways to kill fungi. <em>Candida auris</em> and other fungi use three common cellular tricks to overcome treatments. Luckily, exciting new research hints at ways we can still fight this fungus.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/VOn5Udfx7eQ?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Drug-resistant <em>Candida auris</em> infections are on the rise in the U.S. and around the world.</span></figcaption>
</figure>
<h2>Targeting the sensitive parts of fungal cells</h2>
<p>Fungal cells contain a structure called a <a href="https://doi.org/10.1128/microbiolspec.funk-0035-2016">cell wall</a> that helps maintain their shape and protects them from the environment. Fungal cell walls are constructed in part from several different types of polysaccharides, which are long strings of sugar molecules linked together. </p>
<p>Two polysaccharides found in almost all fungal cell walls are <a href="https://doi.org/10.1016/j.mib.2010.05.002">chitin</a> and <a href="https://doi.org/10.1016/j.tcsw.2019.100022">beta-glucan</a>. The fungal cell wall is an attractive target for drugs because human cells do not have a cell wall, so drugs that block chitin and beta-glucan production will have fewer side effects. </p>
<p>Some of the most common drugs used to treat fungal infections are called <a href="https://doi.org/10.4103%2F0253-7613.62396">echinocandins</a>. These drugs stop fungal cells from making beta-glucan, which significantly weakens their cell wall. This means the fungal cell can’t maintain its shape well. While the fungus is struggling to grow or is breaking apart, your immune system has a much better chance of fighting off the infection. </p>
<h2>How fungi become drug resistant</h2>
<p>Unfortunately, some strains of <em>Candida auris</em> are resistant to echinocandin treatment. But how does the fungus actually do it? For decades, scientists have been studying how fungi overcome drugs designed to weaken or kill them. In the case of echinocandins, <em>Candida auris</em> commonly uses three tricks to beat these treatments: <a href="https://doi.org/10.1128/AAC.00238-18">hide</a>, <a href="https://doi.org/10.1101%2Fcshperspect.a019752">build</a> and <a href="https://doi.org/10.3389/fmicb.2019.02573">change</a>. </p>
<p>The first trick is to hide in a complex mixture of sugars, proteins, DNA and cells <a href="https://doi.org/10.1128/msphere.00458-19">called a biofilm</a>. Made with irregular 3D structures, biofilms have lots of places for cells to hide. Drugs aren’t good at penetrating biofilms, so they can’t access and kill cells deep inside. Biofilms are especially problematic when they <a href="https://doi.org/10.3390/antibiotics4010001">grow on</a> <a href="https://doi.org/10.2147/ijn.s353071">medical equipment</a> like ventilators or catheters. Once free of a biofilm, cells that have gained the ability to resist the drugs a patient was taking become more dangerous.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of two types of Candida attaching to each other" src="https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=300&fit=crop&dpr=1 600w, https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=300&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=300&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=377&fit=crop&dpr=1 754w, https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=377&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/523471/original/file-20230428-26-n4nxfs.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=377&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This image shows <em>Candida albicans</em> (red) producing branching filaments that allow it to attach to <em>Candida glabrata</em> (green), forming biofilms. Both of these species can cause infections in people.</span>
<span class="attribution"><a class="source" href="https://flic.kr/p/HE7JbY">Edgerton Lab, State University of New York at Buffalo/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span>
</figcaption>
</figure>
<p>The second trick fungi use to evade treatment is to build cell walls differently. Fungal cells treated with echinocandins can’t make beta-glucan. So instead, they start to <a href="https://doi.org/10.3109/13693786.2011.577104">make more chitin</a>, another important polysaccharide in the fungal cell wall. Echinocandins are unable to stop chitin production, so the fungus is still able to build a strong cell wall and avoid being killed. While there are some drugs that can <a href="https://doi.org/10.3390/jof6040261">stop chitin production</a>, none are currently approved for use in people. </p>
<p>The third trick fungi rely on is to <a href="https://doi.org/10.3389/fmicb.2019.02788">change the shape of the</a> <a href="https://doi.org/10.1093/cid/civ791">beta-glucan production enzyme</a> so echinocandins cannot block it. These mutations allow beta-glucan production to continue even in the presence of the drug. It is not surprising that <em>Candida</em> uses this trick to resist antifungal drugs since it is <a href="https://doi.org/10.1111%2Fnyas.12831">very effective</a> at keeping the cells alive. </p>
<h2>New tactics to fight fungi</h2>
<p>What can be done to treat echinocandin-resistant fungal infections? Thankfully, scientists and physicians are researching new ways to kill <em>Candida auris</em> and similar fungi. </p>
<p>The first approach is to find new drugs. For example, there are two drugs in development, <a href="https://doi.org/10.3390/antibiotics9050227">rezafungin</a> and <a href="https://doi.org/10.4155%2Ffmc-2018-0465">ibrexafungerp</a>, that appear to be able to stop beta-glucan production even in fungi resistant to echinocandins. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of budding yeast cells" src="https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/523474/original/file-20230428-14-z7579n.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This microscopy image shows budding yeast cells.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/budding-yeast-cell-in-gram-stain-royalty-free-image/1464904014">toeytoey2530/iStock via Getty Images Plus</a></span>
</figcaption>
</figure>
<p>A complementary approach my research group is exploring is whether a class of enzymes called <a href="https://doi.org/10.1007/s11274-016-2068-6">glycoside hydrolases</a> might also be able to combat drug-resistant fungi. Some of these enzymes actively destroy the fungal cell wall, breaking apart both beta-glucan and chitin at the same time, which could potentially help prevent fungi from surviving on medical equipment or on hospital surfaces.</p>
<p>My lab’s work on discovering enzymes that strongly degrade fungal cell walls is part of a new strategy to combat antifungal resistance that uses a combination of approaches to kill fungi. But the end goal of this research is the same: having a physician tell you, “You’ve got a fungal infection, but we have a good treatment for it now.”</p><img src="https://counter.theconversation.com/content/203495/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jeffrey Gardner receives funding from the National Science Foundation (NSF) and the National Institutes of Health (NIH).</span></em></p>Multidrug-resistant fungal infections are an emerging global health threat. Figuring out how fungi evade treatments offers new avenues to counter resistance.Jeffrey Gardner, Associate Professor of Biological Sciences, University of Maryland, Baltimore CountyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/892172018-02-22T11:39:38Z2018-02-22T11:39:38ZStarting with Mother Nature’s designs will speed up critical development of new antibiotics<figure><img src="https://images.theconversation.com/files/207328/original/file-20180221-132642-keuhqw.jpg?ixlib=rb-1.1.0&rect=4%2C144%2C2823%2C1814&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">High-tech ways to scan nature's own creations.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/bioassay-using-liquid-handler-3067482">Caleb Foster/Shutterstock.com</a></span></figcaption></figure><p><em>“I did not invent penicillin. Nature did that. I only discovered it by accident.” - Alexander Fleming</em></p>
<p>Natural products have been the basis of medicine for centuries. Aspirin is based on a chemical in <a href="https://www.pharmaceutical-journal.com/news-and-analysis/infographics/a-history-of-aspirin/20066661.article">willow tree bark</a>. Morphine comes from the <a href="https://www.ncbi.nlm.nih.gov/pubmed/17152761">opium plant</a>. Penicillin was discovered <a href="https://doi.org/10.11622/smedj.2015105">in a mold</a>.</p>
<p>Natural products used in drug therapies are complex, diverse, highly specialized compounds produced by living things. Many evolved as defense mechanisms against other organisms. Certain microbes, for example, spew out potent antibacterial toxins that kill competing microbe species. Streptomycin, chloramphenicol and tetracycline – three of the most widely used antibiotics – were all discovered in <a href="https://doi.org/10.1016/j.cub.2009.04.001">soil bacteria</a>. Nature is the grand architect behind a <a href="https://doi.org/10.1021/acs.jnatprod.5b01055">major</a> <a href="https://doi.org/10.4236/pp.2013.43A003">proportion</a> of modern drugs.</p>
<p>At a time when antibiotic-resistant infections are running rampant, the need for effective new drugs is acute. Every year, <a href="https://www.cdc.gov/drugresistance/index.html">drug-resistant bacteria cause</a> over 2 million infections and 23,000 deaths in the United States alone. And yet, despite their effectiveness, pharmaceutical companies often overlook natural compounds, instead focusing on subpar synthetic ones. Using current technologies to revisit natural products could help researchers identify badly needed new drugs, particularly antibiotics.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/207329/original/file-20180221-132680-wxbrfi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/207329/original/file-20180221-132680-wxbrfi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/207329/original/file-20180221-132680-wxbrfi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=371&fit=crop&dpr=1 600w, https://images.theconversation.com/files/207329/original/file-20180221-132680-wxbrfi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=371&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/207329/original/file-20180221-132680-wxbrfi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=371&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/207329/original/file-20180221-132680-wxbrfi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=466&fit=crop&dpr=1 754w, https://images.theconversation.com/files/207329/original/file-20180221-132680-wxbrfi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=466&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/207329/original/file-20180221-132680-wxbrfi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=466&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Some of Alexander Fleming’s original penicillin mold.</span>
<span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/Britain-Penicillin-Mold/ed84ae41f06145cba41990abd847e6ec/2/0">AP Photo/Alastair Grant</a></span>
</figcaption>
</figure>
<h2>The first ‘golden age’ of antibiotics</h2>
<p>Fleming’s discovery of penicillin in 1929 launched the antibiotic “<a href="https://dx.doi.org/10.1155/2006/707296">golden age</a>.” In the years surrounding World War II, the pharmaceutical industry churned out dozens of new antibiotics in over <a href="https://doi.org/10.1111/j.1476-5381.2011.01250.x">20 unique categories</a>. A few were engineered in the lab, but most were discovered in microbes. These new drugs led to a dramatic decrease in bacterial infections worldwide, increasing the average life expectancy by <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378521/">several</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354621/">decades</a>. Things were looking good.</p>
<p>Sadly, it couldn’t last. In the 1960s, the discovery of new antibiotic categories, or classes, came to a screeching halt. Since then, <a href="https://doi.org/10.1111/j.1476-5381.2011.01250.x">only two new classes</a> have come to market. After years of blasting infections with the same classes of antibiotics, organisms had evolved resistance mechanisms; many existing antibiotics stopped working. Having picked the low-hanging fruit of antibacterials, our arsenal was drying up. Bacteria are developing resistance faster than we’re coming up with new weapons.</p>
<h2>Rise of high-throughput screening</h2>
<p>Researchers <a href="https://doi.org/10.1038/sj.bjp.0707373">in the 1980s</a> started to focus on a rising technology called high-throughput screening (HTS). Automated systems test thousands – even millions – of compounds per year. The goal is to identify compounds that would spell bad news for infectious agents. Researchers observe how effective each compound is against a potential target – for example, in disrupting the bacterial cell wall or hindering its ability to synthesize DNA, RNA or protein. Many HTS systems aim for just one of these processes at a time in a plastic multi-well plate.</p>
<p>Some top-of-the-line HTS robots can push through <a href="https://academic.oup.com/bib/article/16/6/974/225604">100,000 compounds per day</a>. The idea is that by screening millions of compounds, researchers are bound to find some with antimicrobial activity.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/207132/original/file-20180220-116327-1q1jjf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/207132/original/file-20180220-116327-1q1jjf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/207132/original/file-20180220-116327-1q1jjf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=398&fit=crop&dpr=1 600w, https://images.theconversation.com/files/207132/original/file-20180220-116327-1q1jjf.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=398&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/207132/original/file-20180220-116327-1q1jjf.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=398&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/207132/original/file-20180220-116327-1q1jjf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=500&fit=crop&dpr=1 754w, https://images.theconversation.com/files/207132/original/file-20180220-116327-1q1jjf.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=500&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/207132/original/file-20180220-116327-1q1jjf.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=500&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Automation lets robots screen massive amounts of compounds very quickly.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Chemical_Genomics_Robot.jpg">Maggie Bartlett, National Human Genome Research Institute</a></span>
</figcaption>
</figure>
<p>To save costs, pharmaceutical companies put together compound libraries: huge databases of small molecules in just about every configuration they could think of. Despite their proven track record, many companies decided natural products had <a href="http://dx.doi.org/10.4236/pp.2013.43A003">low economic value</a> and instead turned to cheaper synthetic chemicals. These are screened against pathogen targets in the search for “hits”: cases where the database molecule affects the infectious agent.</p>
<h2>Prioritizing quantity over quality</h2>
<p>It turns out, scientists aren’t as good at designing antibiotics as we’d hoped. Compared to natural products, synthetic compounds simply haven’t been a high-quality source of drugs. Even after years of fine-tuning HTS, success rates for novel compounds are <a href="https://doi.org/10.1016/j.bmcl.2015.07.014">extremely low</a>. Pharmaceutical companies might spend years looking for drug candidates and still come up empty. </p>
<p>In fact, natural products still <a href="https://doi.org/10.1021/acs.jnatprod.5b01055">account for half</a> of newly discovered drugs since the 1980s, and approval rates for naturally derived products <a href="https://doi.org/10.1016/j.bmcl.2015.07.014">are climbing</a>, even though very few are screened compared to synthetic compounds.</p>
<p>Time and money are precious resources in drug development; it takes 10 to 15 years and <a href="http://www.sciencemag.org/site/products/ddbt_0207_Final.xhtml">millions of dollars</a> – <a href="https://doi.org/10.1016/j.bmcl.2015.07.014">even</a> <a href="https://doi.org/10.1111/j.1476-5381.2010.01127.x">billions</a> – to develop a single drug from “farm-to-table.” There are four major steps of drug development:</p>
<ol>
<li>Screen compound library and identify “hits”;</li>
<li>Confirm hits with further testing, at which point they become “lead compounds”;</li>
<li>Advance leads <a href="https://www.fda.gov/ForPatients/Approvals/Drugs/default.htm">through clinical trials</a>;</li>
<li>And finally, successful release of the drug.</li>
</ol>
<p>From beginning to end, maybe <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772997/#S3title">1 in 10 million</a> <a href="https://doi.org/10.1177/1087057106292473">compounds screened</a> – and that’s a generous estimate – will become a <a href="https://www.bio.org/sites/default/files/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf">successful drug for infectious diseases</a>. This number has not significantly improved over the years.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/207151/original/file-20180220-116360-singh4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/207151/original/file-20180220-116360-singh4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/207151/original/file-20180220-116360-singh4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/207151/original/file-20180220-116360-singh4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/207151/original/file-20180220-116360-singh4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/207151/original/file-20180220-116360-singh4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/207151/original/file-20180220-116360-singh4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/207151/original/file-20180220-116360-singh4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">A robot plate carousel could hold natural compounds just as easily as synthesized ones.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/64860478@N05/37821530755">Daniel Soñé Photography, LLC</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<h2>Bring back the old-school methods</h2>
<p>One reason natural products are such a promising resource for new drugs is that they are <a href="https://doi.org/10.3892/br.2017.909">more biologically relevant</a> than synthetics; they’re ready-made to be active within cells. They contain fewer heavy metals and can be <a href="http://dx.doi.org/10.4236/pp.2013.43A003">extremely stable</a>. Most importantly, because of their high complexity and diversity, a single natural compound often simultaneously targets multiple bacterial processes (for instance, both the cell wall and protein synthesis), making it <a href="https://doi.org/10.1016/S0031-9422(00)00230-2">less susceptible to resistance</a>.</p>
<p>In comparison, high-throughput screening usually involves pinpointing only single targets – for instance, a particular bacterial enzyme or viral protein. Then, follow-up experiments will determine whether the drug-target interaction actually works within a cell, and not just in a test tube. This is incredibly inefficient and is a crucial limitation of classic HTS.</p>
<p>The most effective antibiotics are discovered by testing for antibacterial, antifungal or antiviral activity first, and then teasing apart the molecular mechanism. This means turning the focus back to bacterial assays, where compounds are tested in live bacterial cell cultures from the start. Newer HTS systems do target whole-cell systems, but much of the pharmaceutical industry still persists in using synthetic small-molecule libraries and shies away from naturally derived products.</p>
<p>This doesn’t mean that HTS has no place in drug development. But a meal is only as good as its ingredients, and high throughput is useless without high-quality compounds.</p>
<p>There are certainly barriers to natural product research. When it comes to plant-based chemicals, for example, high throughput <a href="https://doi.org/10.3892/br.2017.909">can be a challenge</a>; purifying a specific chemical from pulverized plant material can be difficult to do the exact same way every time. Natural products are also difficult to patent, so for pharmaceutical companies, large compound libraries are more <a href="https://doi.org/10.3390/metabo2020303">economically</a> <a href="https://doi.org/10.3389/fphar.2015.00237">viable</a>.</p>
<p>However, with improved technology, HTS of natural products is becoming a reality, particularly when it comes to compounds <a href="https://doi.org/10.1177/1087057114555846">produced by microbes</a>. Mass production is also getting easier; not just for bacteria, which are straightforward to culture on a large scale, but for plant-based chemicals too. In 2006, for example, <a href="https://doi.org/10.1038/nature04640">researchers at UC Berkeley</a> found a way to engineer yeast to mass-produce the precursor for artemisinin, the antimalarial and <a href="https://www.scidev.net/asia-pacific/tb/news/malaria-drug-artemisinin-against-tb.html">anti-TB</a> compound that comes from the herb <em>Artemisia annua</em>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/207152/original/file-20180220-116368-100btyw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/207152/original/file-20180220-116368-100btyw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/207152/original/file-20180220-116368-100btyw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/207152/original/file-20180220-116368-100btyw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/207152/original/file-20180220-116368-100btyw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/207152/original/file-20180220-116368-100btyw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=565&fit=crop&dpr=1 754w, https://images.theconversation.com/files/207152/original/file-20180220-116368-100btyw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=565&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/207152/original/file-20180220-116368-100btyw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=565&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Plants and microbes likely hold many unknown but useful compounds.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/ripplestone/3720240082">Trisha</a>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<h2>Potential gold mines for natural compounds</h2>
<p>There is a huge area of untapped resources for natural anti-pathogenic molecules. A very small portion – <a href="https://doi.org/10.4236/pp.2013.43A003">less than 15 percent</a> – of terrestrial plants have been explored for natural product research; strikingly, <a href="https://doi.org/10.4236/pp.2013.43A003">less than 1 percent</a> of the microbial world has been tapped.</p>
<p>Almost <a href="https://doi.org/10.1038/417141a">two-thirds of natural products</a> come from a group of bacteria called actinomycetes, which include the streptomycetes. They produce antibacterial, antifungal, antiparasitic, immunosuppressant and anti-viral compounds. Potent anti-viral compounds have been found in fungi, plants and even <a href="http://pubs.rsc.org/en/content/articlehtml/2015/np/c4np00085d#sect999">marine sponges</a>. Drugs could potentially even come from <a href="http://doi.org/10.1074/jbc.R116.762906">the microbiome in our own gut</a>.</p>
<p>Currently, I study certain plant-based extracts, traditionally used as anti-inflammatories in non-Western medicine, that actually have antiviral properties. <a href="https://doi.org/10.4103/0973-7847.79105">Feverfew</a>, for example, can protect cells against viruses like <a href="https://doi.org/10.1186/1471-2105-12-S13-S22">herpes simplex</a> and <a href="https://doi.org/10.3892/mmr.2012.959">Epstein-Barr</a> by inhibiting inflammatory pathways. Artemisinin, mentioned earlier as an antimalaria drug, also has broad-spectrum activity against <a href="https://doi.org/10.1086/591195">many different viruses</a>.</p>
<p>Drug-resistant infections are a major <a href="http://www.who.int/mediacentre/factsheets/antibiotic-resistance/en/">global health threat</a>. It is critical that drug developers push for high-quality source material in their search for new drugs. It’s time to use technology to revive and upgrade tried-and-true methods.</p><img src="https://counter.theconversation.com/content/89217/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Natalie Jones Slivinski does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Pharmaceutical companies focus on small molecules they’ve devised – and can easily patent. But nature’s already come up with many antibacterial compounds that drug designers could use to make medicines.Natalie Jones Slivinski, Virology Research Scientist, University of WashingtonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/456092015-08-21T05:34:40Z2015-08-21T05:34:40ZEnemy within: the fungus that lives in your mouth and kills as many as MRSA<figure><img src="https://images.theconversation.com/files/92432/original/image-20150819-10870-uull12.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Candida albicans lives in the mouth or digestive tract of 50% of people.</span> <span class="attribution"><a class="source" href="https://en.wikipedia.org/wiki/Candida_albicans#/media/File:Candida_albicans_2.jpg">Graham Beards</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>On hearing the word “fungi” most people will probably think of pizza <em>al funghi</em> or a portobello mushroom burger. Incidentally, roughly half of the people salivating about these dishes will also carry a fungus called <em>Candida albicans</em> in their <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1479199/">mouths or digestive tracts</a> where it lives quietly, invisibly to the human eye, without causing disruptions or symptoms.</p>
<p>But <em>Candida albicans</em> does not always go unnoticed. While most people carrying the fungus will go through life without ever learning the scientific name of their innocuous tenant, also called a “commensal”, some do encounter it as the common cause of oral thrush, nappy rush or vaginal yeast infections. Indeed, <a href="http://www.ncbi.nlm.nih.gov/pubmed/17560449">75% of women</a> will experience at least one episode of yeast infection throughout their lifetime.</p>
<p>It gets worse. Changes to a person’s immune defences can help <em>Candida albicans</em> cause life-threatening infections of the blood stream and the inner organs. Patients suffering HIV/AIDS or those undergoing cancer chemotherapy or solid organ transplants or babies with low birth weight are at risk of contracting this infectious disease. <em>Candida albicans</em> is the most commonly acquired fungal infections in a hospital setting, <a href="http://www.ncbi.nlm.nih.gov/pubmed/19744519">particularly among patients in intensive care units</a>. </p>
<h2>Global infection</h2>
<p>The consequences are dire. Each year, <a href="http://www.ncbi.nlm.nih.gov/pubmed/19744519">around 700 patients die</a> of <em>Candida albicans</em> infections in the UK alone. This is <a href="https://www.gov.uk/government/statistics/mrsa-mssa-and-e-coli-bacteraemia-and-c-difficile-infection-annual-epidemiological-commentary">about as many</a> as those that die of infections caused by Methicillin Resistant Staphylococcus aureus or MRSA. But while rates of MRSA have been falling, rates of <em>Candida albicans</em> infections remained steady over a five-year period. In addition to the human suffering, each <em>Candida albicans</em> infection adds about £16,500 extra to an adult’s hospital bill as it prolongs the time the patient needs to spend in the intensive care unit by <a href="http://www.ncbi.nlm.nih.gov/pubmed/19744519">more than five days</a>.</p>
<p>However, <em>Candida albicans</em> infections, like many other fungal diseases, are a global problem. Around the world, 400,000 people suffer each year from <a href="http://stm.sciencemag.org/content/4/165/165rv13">infections of the blood stream and the organs</a> – and this number is rising. With the advent of new medical procedures that has led to an increase in people with compromised immune systems, the incidence rate of <em>Candida albicans</em> infections is on the rise as well. A review of 750m hospitalisations in the US revealed that the rate of fungal bloodstream infections has <a href="http://www.ncbi.nlm.nih.gov/pubmed/12700374">increased by more than 200%</a> within a couple of decades. With mortality rates of up to 75%, the human burden is substantial, demanding effective therapeutic strategies. There are, however, two major obstacles that severely hamper our ability to prevent or treat life-threatening <em>Candida albicans</em> infections.</p>
<h2>Human colonisation</h2>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/92436/original/image-20150819-10836-tjubgp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/92436/original/image-20150819-10836-tjubgp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=405&fit=crop&dpr=1 600w, https://images.theconversation.com/files/92436/original/image-20150819-10836-tjubgp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=405&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/92436/original/image-20150819-10836-tjubgp.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=405&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/92436/original/image-20150819-10836-tjubgp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=509&fit=crop&dpr=1 754w, https://images.theconversation.com/files/92436/original/image-20150819-10836-tjubgp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=509&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/92436/original/image-20150819-10836-tjubgp.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=509&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Say cheese: oral thrush.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Oral_thrush_Aphthae_Candida_albicans._PHIL_1217_lores.jpg">CDC</a></span>
</figcaption>
</figure>
<p>Preventing transmission of <em>Candida albicans</em> is next to impossible because the enemy lives within. While the spread of viral or bacterial infections can often successfully be averted by quite simple measures, such as washing the hands or using condoms, these are not an option for a fungus that colonises humans during birth or shortly after – passing through the <a href="http://www.ncbi.nlm.nih.gov/pubmed/18277930">birth canal</a>, or possibly through <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC347808/">nursing</a>, or through the close mother-child relationship in general (<a href="http://www.ncbi.nlm.nih.gov/pubmed/10495712">for example by licking pacifiers</a>) provide ample opportunities for the fungus to colonise our mouths as babies and for it to eventually enter our digestive tract.</p>
<h2>From mouth mate to death rate</h2>
<p>The transition between living in and on humans without causing trouble to suddenly causing a life-threatening disease is a puzzle. Scientists are only just now beginning to unravel how <em>Candida albicans</em> flips the switch that turns it into a deadly threat, requiring immediate medical intervention and the application of antifungal drugs. Recent research showed that <em>Candida albicans</em> <a href="http://www.ncbi.nlm.nih.gov/pubmed/23892606">co-opts a molecular signal</a> that usually regulates mating in the fungus. This signal down-regulates any fungal features associated with causing disease. This way, scientists assume, <em>Candida albicans</em> can be present in the intestines without alerting the immune system to its presence. Curiously, this molecular switch is also controlled by the nutrient composition in the human gut. The exact nature of this, however, remains enigmatic.</p>
<p>Which leads to the second major problem associated with <em>Candida albicans</em> infections. They are difficult to treat because only few drugs that kill fungi exist. The reason for why there are so many fewer anti-fungal than antibacterial drugs lies in our shared evolutionary history. Fungi are <a href="http://www.ncbi.nlm.nih.gov/pubmed/8469985">more closely related to humans than bacteria</a>, which means that there are less specific molecules in the fungus that can be targeted to stop the fungus from growing. This, in combination with the challenges of drug design in general, dramatically slows down the development of anti-fungal drugs. So much so that it has been <a href="http://www.sciencemag.org/content/347/6229/1414">almost ten years</a> since the last anti-fungal drug class received approval.</p>
<p><em>Candida albicans</em> is not the only fungus that threatens human health and life. The top ten most aggressive fungi kill as many, if not more, people as <a href="http://stm.sciencemag.org/content/4/165/165rv13">tuberculosis or malaria</a>. Worldwide, an estimated 1.5m patients die from fungal infections each year.</p><img src="https://counter.theconversation.com/content/45609/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Stephanie Diezmann receives funding from the University of Bath, MRC, BBSRC, Royal Society.</span></em></p>A seemingly harmless oral fungus can get out of hand but there aren’t as many drugs as you may think to deal with it.Stephanie Diezmann, Lecturer, Milner Centre for Evolution, University of BathLicensed as Creative Commons – attribution, no derivatives.