Last summer, a UK-based hospital was forced to close its intensive care unit after 50 patients became infected with a highly drug-resistant fungus, Candida auris, resulting in 3 deaths. Since then, more than 200 cases have been reported in more than 55 hospitals across the UK, and Candida auris infections have been detected in at least 15 countries worldwide.
While Candida auris has attracted significant media coverage, it is not the only invasive fungus we should be aware of. Invasive or systemic fungal diseases represent a rapidly growing health problem amongst at-risk groups of individuals, such as those with severely compromised immune systems, including organ transplant recipients, HIV+/AIDS patients, and individuals undergoing harsh chemotherapy regimes, to name a few.
Remarkably, these diseases are unheard of by many, despite the fact that they cause more deaths per year than malaria. To put that into perspective, the World Health Organisation estimated 438,000 deaths due to malaria in 2015, while at least 1.6 million people are estimated to die from fungal infections worldwide annually. This means that fungal infections cause almost 70 times more deaths per year than antibiotic-resistant bacterial infections, with the latter associated with approximately 23,000 deaths annually worldwide.
What is it?
For many of us, the words ‘fungal infection’ are a reminder of irritating and embarrassing skin conditions such as athlete’s foot, ringworm and vaginal thrush. These fungal infections, although uncomfortable and unsightly, are superficial, and are usually restricted to the outer layers of the skin, nails and hair. Superficial infections are often readily treatable, and although the infections can reoccur, they are rarely life threatening. Complications that arise from superficial fungal infections are usually provoked by co-existing conditions, including but not limited to, inflammatory skin diseases, circulatory disorders and diabetes.
Systemic fungal disease occurs when certain fungal species gain entry to and rapidly spread throughout the body in the absence of an intact immune system, invading both the bloodstream and organs. It’s estimated that these infections affect around 2 million people annually worldwide, and the clinical outcomes depend to a large extent on the underlying disease and immune status of the patient. Overall survival rates are poor, with an estimated 50% survival for all treated invasive fungal infections in non-AIDS patients in the developed world.
Although a number of fungal species are emerging as invasive pathogens, the main players in this territory are species of Cryptococcus, Aspergillus and Candida e.g., Cryptococcus neoformans, Aspergillus fumigatus and Candida albicans, respectively. These fungi are responsible for the diseases known as cryptococcal meningitis, invasive aspergillosis and invasive candidiasis. Because these fungi are usually harmless to healthy individuals, they are considered to be opportunistic pathogens, only establishing systemic and life-threatening infections when other conditions compromise the immune system. In other words, they strike when the body’s defences are down.
A number of fungal species, including those listed above, can also cause chronic infections in predisposed individuals. For example, chronic pulmonary aspergillosis (caused by Aspergillus fumigatus) is a lung condition that may occur in patients with past or present lung disease, and is believed to affect more than 3 million people worldwide. Although not necessarily life-threatening, chronic pulmonary aspergillosis is marked by progressive respiratory difficulty and weight loss, often resulting in regular hospitalisation, life-long treatment, and a reduction in life quality.
What can we do about invasive fungal infections?
Well, the obvious answer is to treat affected individuals with an appropriate antifungal drug. Unfortunately, this is not as straightforward as it sounds. Currently, there are 3 main classes of antifungal drugs available, the polyenes (e.g. amphotericin B), the azoles (e.g. fluconazole) and the echinocandins (e.g. caspofungin). While these groups collectively encompass most of the desired features of an ideal antifungal, there is no one drug that ticks all the boxes. Resistance development is also a growing obstacle for the most widely used class, the azoles.
In addition to the problem of drug resistance, the weakened state of patients with invasive fungal disease may narrow their eligibility for treatment with the current drugs. Ineligibility for some of the current therapies can arise for a number of reasons, such as the risk of serious side effects e.g., amphotericin B can cause severe kidney damage, or detrimental interactions with other drugs e.g., the absorption of the azoles is reduced during co-administration with a number of other drugs.
New antifungals urgently needed
On top of the issues outlined above, the effective management of invasive fungal infections is often hampered by delays in proper diagnosis. Such delays, coupled with the lack of a one-size-fits-all antifungal means that a considerable number of patients may actually miss the boat when it comes to timely effective antifungal treatment. These patients could benefit greatly from an antifungal that is safe, has low or no propensity for developing resistance, and is able to treat the majority of fungal infections (i.e. a broad spectrum drug), before a diagnosis is reached. Upon diagnosis, this drug could then be supplemented or replaced by a superior drug as appropriate. In other words, we need to expand the current antifungal toolbox to cater for all situations. The urgent need for new antifungals has been highlighted numerous times by experts in the field, and the development of novel drugs targeting fungal infections is the subject of many research laboratories worldwide.
The quest for new antifungal drugs
Developing new drugs to treat any microbial (i.e. bacterial or fungal) disease is no easy task, but finding unique drug targets in the pathogenic organism is a good place to start. A unique antifungal drug target simply refers to a part or characteristic of a fungal cell that can be modified by a drug, to either inhibit the growth of or kill that fungus, ideally without damaging human or animal cells or tissue in the process.
Because fungal cells are quite similar to human and animal cells, intense efforts are required to find unique and realistic antifungal targets. The current antifungal drugs target either the cell wall or the fungal cell membrane, and while modifications to upgrade and improve these drugs are ongoing, research in recent years has sought after novel antifungal drug targets.
The hunt for new antifungal drug targets is greatly aided by advances in DNA sequencing and genetic engineering technologies. Today, researchers from all corners of the world are working hard to develop novel antifungals, and technology to explore new drugs targets is continuously improving.
Karen O’Hanlon Cohrt is a Science Writer and Editor based in Denmark. She has a PhD in Biotechnology from Maynooth University, Ireland, and can be found on Twitter @KarenOHCohrt and https://www.kcwritingforscience.com/