The emergence of anti-fungal drug resistance – Medical News Bulletin

A recent review in Science described an alarming increase in resistance to antifungal drugs used for plant, animal, and human applications.

Fungal pathogens can have devastating effects on our agriculture, livestock, and global health. Globally, fungal pathogens result in about 20% crop yield wastage prior to harvest and about 10% post harvest damage. In terms of human health, the burden of global fungal disease rivals TB and HIV.

Pathogenic fungi pose multiple threats to humanity

Despite stringent antifungal measures to prevent the spread of these pathogens, this species is surprisingly common. The main reason is a very flexible fungal genome that can adapt quickly to the stresses induced by antifungal medications.

Another reason is agricultural monoculture, which provides a predictable and uniform environment for the growth of fungal pathogens. Preventative antifungal treatments in certain human diseases may also give rise to antifungal resistance, similar to what is observed in cases of antibiotic resistance against bacterial pathogens.

The limited arsenal of antifungal strategies

research into the development of antifungal drugs, only limited counter-strategies have been developed to combat fungal pathogens. These strategies can be classified into three major mechanisms. Disturbance of the structural integrity of fungal cell walls, interference in the metabolism of the constitutive elements of maintenance and synthesis of the fungal cell wall (biosynthesis of ergosterol and glucans), blockage of pyrimidine biosynthesis (building blocks of DNA inhibiting the biosynthesis of pyrimidines) exerting pressure on DNA replication and preventing the proliferation of fungal pathogens)

Factors Promoting Fungus Resistance

L & # 39; Large scale pesticide application may challenge the natural defenses of plants and allow fungal pathogens to easily adapt to the predictive mode of actions used in conventional antifungal medications previously used. In humans, treatment of HIV and other medical interventions that compromise the immune system may allow fungal pathogens to escape surveillance and cause opportunistic infections. Ease of transport can allow fungal pathogen carriers to cross geographical boundaries and contribute to the spread of fungal diseases. An example of this includes Candida auris a pathogenic fungus that was first restricted to Japan but is now a fungal pathogen emerging recently in many nosocomial infections worldwide.

Undiscriminated and Unjustified Use Fungal drugs as a preventive measure may allow pathogens to be pre-sensitized to the antifungal drug and modify their genome to develop a mechanism of resistance. This was observed in the Candida glabrate a pathogen associated with antifungal resistance due to the repeated use of azoles (class of antifungal drugs). Large-scale resistance against antifungal drugs has also been observed in plant pathogens. Resistance to MBC, which is a resistance against a class of drugs called benzimidazoles, is observed in more than 90 plant pathogens. Similarly, within ten years, at least 17 new plant pathogens have been shown to be resistant to succinate dehydrogenase inhibitors

Molecular basis of antifungal resistance

Fungal pathogens develop many resistances. One of the most common mechanisms of anti-fungal resistance is the emergence of new mutations that compromise the target of the anti-fungal drug. Mutations are hereditary modifications of DNA that alter the sequence of the coding region which, in turn, alters the protein sequence that is translated from the mutated DNA chain. Such mutations somehow prevent the interaction of the drug with the variant target that emerges post-mutation.

For example, a single amino acid mutation in cytochrome b was found to cause anti-fungal resistance in at least 20 plant species. Some fungal pathogens "spit" anti-fungal drugs using efflux pumps that drive drugs through a protein channel. Some fungal pathogens use Hsp90 chaperone proteins to overcome the stress induced by anti-fungal drugs. It is a protein that can help certain fungi induce drug-inducing toxicity by activating key chaperone stress pathways and key proteins – possibly allowing the pathogen to survive the attack of the fungi. antifungal medications

how do we fight this growing anti-fungal resistance? Many strategies are being explored to counteract fungi resistance. The first strategy is to intensify their research efforts to develop new classes of antifungal drugs with new modes of action. This has resulted in many new antifungal drugs reaching Phases 1 and 2 of the clinical trials. Another way to bypass the anti-fungal resistance is to use a mixture of several antifungal medications with distinct modes of action. The third way is to adapt molecular diagnostic methods to target anti-fungal drugs with greater precision. This would prevent the large-scale use and development of antifungal gene resistance.

Although there are several methods to counter mushroom resistance, there is no single strategy for dealing with various resistance mechanisms. Additional research to control fungi resistance is needed to prevent losses from fungal pathogens.

Written by Vinayak Khattar, Ph.D., MBA

Reference: Fisher M, Hawkins N, D Buckwheat, Gurr S. Global emergence of resistance to antifungal drugs endangers health human and food security. Science. 2018; 360 (6390): 739-742.