The epigenetics of antifungal resistance

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Decades of antibiotic and antifungal use have had a dramatic impact on the global microbiome, with ramifications for agriculture and human health. Concerns are growing but no systematic action plan is planned. That’s not to say there isn’t a ray of hope.

While still largely confined to immunocompromised patients, fungal infections are a looming public health crisis. Invasive candidiasis is increasingly caused by multi-resistant non albicans yeasts and nearly 60% of C. parapsilosi sampled in South Africa are now resistant to fluconazole, at an alarming but not abnormally high level (Friedman, 2019).

For agriculture, fungal pathogens pose a more immediate threat. Very resistant species like F.oxysporumresponsible for banana Panama disease, could ruin the livelihoods of millions of farmers (Ordonez, 2015).

Rising global temperatures will only accelerate the emergence of new threats. Catastrophic events caused by fungi are not unknown. Between 1845 and 1852, P. infestans one million deaths and the emigration of 2.1 million Irish.

The decimation of a staple or cash crop becomes more likely as mycologists discover not only newly resistant pathogens, but also newly pathogenic species (Nnadi, 2021; Fischer 2012).

Yet, for now, only four classes of antifungals are commonly used: azoles, polyenes, echinocandins and a single nucleoside analogue, flucytosine (McCarthy, 2019).

Documented genetic changes in bacterial populations do not fully explain antibiotic resistance, prompting researchers to turn their attention to epigenetic processes (Ghosh, 2020). Many of these alterations have been studied in oncological settings, resulting in multiple FDA-approved cancer therapies (Heerboth et. al, 2014).

Common epigenetic modifications include acetylation, methylation, sumoylation, alterations in chromatin structure and, perhaps most promising for infectious disease management, RNA silencing.

These mechanisms, alone or in combination, promote phenotypic plasticity. Rapid epigenetic responses allow unwanted cells (malignant, bacterial or fungal) to buy time while inherited adaptations develop.

Histone deacetylases (HDACs) remove acetyl groups from histones, which are partially responsible for managing cellular stress responses. HDAC inhibition impacts virulence factors such as biofilm formation, fungal growth and host dissemination (Garnaud, 2016; Simonetti, 2007).

Histone acetylation is involved in the development of resistance to antifungals C. albicans; it has been known for decades that trichostatin A, a broad-spectrum drug HDACs inhibitor (HDACi), has antifungal properties; as coordinators of fungal life cycles, targeting histones can reduce virulence, as has been shown with U.maydisbetter known as corn smut (Elías-Villalobos, 2015).

Other epigenetic phenomena, such as RNA silencing, figure prominently in how pathogenic fungi work and how, in the near future, they may be managed.

RNAi signals can affect cells of several organisms. Pathogens use effector proteins and toxins to suppress the host’s innate immunity. The mushroom toolbox was thought to be limited to these factors until Weinberg discovered that B. cinereabetter known as Soft Rot, produces RNAs to disrupt plant immune signaling pathways (Hua, 2018).

In other words, they can be used by a host to defend itself or by a parasite to attack (or vice versa). This line of inquiry was opened in 1998 when Timmons and Fire fed dsRNA-carrying E. coli with nematodes. Host-induced gene silencing (HIGS), under human control, was born.

It has been applied to wilt disease in arabidopsis and cotton. Wilt can kill a tree in a single growing season. This is doubly worrying as no resistance genes have been found in crops like cotton, sunflower and potato (Zhang, 2016).

RNA silencing in M.circinelloides (which does not yet have a more memorable common name) gives us an example of the previously mentioned phenomenon of phenotypic plasticity.

M.circinelloides gains resistance to 5-FOA through sense and antisense RNAs, which silence pyRf and pyRg. This is normally accomplished by genetic mutations at these loci. A similar alteration simultaneously protects it from rapamycin and FK506 (Calo et. al, 2014).

It is essential not only to consider new techniques, but also to know how to improve the effectiveness of existing options. This can be done through epigenetic modulation (Chang et. al, 2019), which has been explored with antibiotic resistant bacteria. It offers a quick way to prolong the usefulness of approved antifungals (Adam, 2008; Ghosh, 2020).

Despite the costs of unpreparedness, relevant diagnostic tests, vaccines, drugs, and basic pathophysiological research remain woefully underfunded (Brown et. al, 2012). Additionally, a dangerous overlap between antifungals used for plants and humans is driving drug resistance, as evidenced by animal pathogens that repeatedly acquire resistance to azoles through agricultural fungicides ( Shepherd, 2017).

If these leads are not pursued now, we will once again find ourselves caught off guard. Unpreparedness is not tenable in a hyperconnected world.

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