antifungal drugs

A recent review in Science has described an alarming rise of resistance in anti-fungal drugs used for plant, animal, and human applications.

Fungal pathogens can have devastating effects on our agriculture, animal husbandry, and global health. Globally, fungal pathogens lead to wastage of about 20% of crop-yields before harvest and about 10% damage post-harvest. In terms of human health, the burden of global fungal disease rivals tuberculosis and HIV.

Pathogenic fungi pose multiple threats to humankind

Despite stringent anti-fungal measures to prevent the spread of these pathogens, research indicates that resistance among fungal species is surprisingly common. The primary reason for this is a highly flexible fungal genome that can adapt rapidly to the stresses induced by anti-fungal drugs.

Another reason is monoculture agricultural practices, which provide a predictable and uniform environment for the fungal pathogens to thrive. Preventive anti-fungal treatments in some human diseases can also give rise to anti-fungal resistance, akin to what is observed in cases of antibiotic resistance against bacterial pathogens.

The limited arsenal of anti-fungal strategies

Despite decades of research in the development of anti-fungal drugs, only limited counter-strategies have been devised to deal with fungal pathogens. These strategies can be broadly classified into three major mechanisms. These include disruption of fungal cell-wall structural integrity, interference in metabolism of building  blocks required for maintenance and synthesis of fungal cell wall (biosynthesis of ergosterol and glucans), blocking pyrimidine biosynthesis (building blocks that make up DNA, therefore inhibiting biosynthesis of pyrimidines puts a pressure on DNA replication and impedes the proliferation of fungal pathogens).

Factors that favor anti-fungal resistance

Broad-scale pesticide application can blunt plants natural defenses and allow fungal pathogens to adapt easily based on the prediction mode of actions utilized in classical anti-fungal drugs employed previously. In humans, the treatment of HIV and other medical interventions that compromise immune system can allow fungal pathogens to escape surveillance and cause opportunistic infections. The ease of transportation can allow “carriers” of fungal pathogens to cross geographical barriers and can contribute to spreading of fungal diseases. Example of this includes Candida auris, a fungal pathogen that was first limited to Japan but is now a recently emerging fungal pathogen found in many hospital-acquired infections around the world.

Indiscriminate and unwarranted use of anti-fungal drugs as preventive measures can allow pathogens to be pre-sensitized to the anti-fungal drug and modify their genome to develop resistance mechanism. This has been observed in Candida glabrate, a pathogen that is associated with anti-fungal resistance due to repeated use of azoles (class of anti-fungal drugs). Large-scale resistance against anti-fungal drugs has been observed in plant pathogens as well. MBC resistance, which is resistance against a class of drugs called benzimidazoles, is observed in more than 90 plant pathogens. Similarly within a span of 10 years at least 17 new plant pathogens developed that were found to be resistant to succinate dehydrogenase inhibitors.

Molecular basis of antifungal resistance

There are many ways fungal pathogens develop resistance. One of the most common mechanisms of anti-fungal resistance is the emergence of novel mutations that compromise the anti-fungal drug target. Mutations are heritable changes in DNA that change the sequence of the coding region which in turn changes the protein sequence that is translated from the mutated DNA string. Such mutations somehow prevent the interaction of the drug with the variant target that emerges post-mutation.

For instance, a single amino-acid mutation within cytochrome b has been found to cause anti-fungal resistance in at least 20 plan pathogen species. Some fungal pathogens actually “spit out” anti-fungal drugs using efflux pumps that drive out the drugs through a protein channel. Some fungal pathogens use Hsp90 chaperone proteins to tide over the stress induced by anti-fungal drugs. This is a protein that can help some fungus mediate drug-inducing toxicity by activating stress-pathways and chaperone key proteins – eventually allowing the pathogen to survive the onslaught of anti-fungal drugs.

Countering anti-fungal resistance

So how do we combat this increasing anti-fungal resistance? There are many strategies that are being explored to counter anti-fungal resistance. The first strategy involves intensifying their research efforts to develop new classes of antifungal drugs with novel modes of actions. This has resulted in many new antifungal drugs reaching phase 1 and 2 of clinical trials. Another way to work around anti-fungal resistance is using a mixture of multiple anti-fungal drugs with distinct modes of actions. The third way is tailoring molecular diagnostic methods to target anti-fungal drugs with greater precision. This would prevent broad scale use and development of generic anti-fungal resistance.

While there may be several methods to counter anti-fungal resistance, there is no single strategy that can be employed to deal with diverse resistance mechanisms. Further research to combat anti-fungal resistance is required to prevent losses due to fungal pathogens.

Written by Vinayak Khattar, Ph.D., M.B.A.

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

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