Why scientists are rethinking the chemical ‘arms race’ against fungi

Why in the News

A study in Nature Communications has characterised the Indian clinical isolates of Candida auris and traced how the pathogen defeats two of the three main antifungal classes. It was carried out by researchers at the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bengaluru, with collaborators at the Indian Institute of Science Education and Research, Thiruvananthapuram, using isolates from the repository of the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh. Earlier work on resistance had been done largely in model systems, and this study established its findings in patient samples. The finding that matters clinically is that the resistance ceiling used to test one of those drugs sits far below the concentration the pathogen can already survive. What follows from it is a rejection of the chemical arms race approach itself, in favour of drugs that disarm a pathogen rather than trying to kill it outright.

What is Candida auris?

1. Type of organism: It is a yeast, meaning a single oval shaped fungal cell, as distinct from molds such as the dermatophytes that grow in long strands.
2. Clinical course: It enters the bloodstream and causes severe infections, most of which are untreatable with the available antifungals.
3. Severity: Those infected suffer a mortality rate of 30 to 40 per cent.
4. Recency: It has become a menace only in the last two decades, with the first report in Japan in 2009, and it is now rapidly emerging as a multidrug resistant pathogen in intensive care units.

Why are fungal infections rising at all?

1. The temperature barrier: Fungi grow best in damp places below 30 degrees Celsius, so bloodstream infections in humans were rare because the pathogens could not survive the body’s 37 degrees Celsius.
2. The warming hypothesis: Global warming places selective pressure on fungi so that only the more heat tolerant survive, and those survivors can also survive inside human bodies once they gain access, which is called the fungal infection mammalian selection hypothesis.
3. Evidence from cold blooded hosts: Fungal infections are common in cold blooded animals with lower body temperatures, which is the comparison the hypothesis rests on.
4. Scale in Indian hospitals: Roughly 20 per cent of infections reported in hospitals are fungal in nature, and most hospitals in India lack the capability and infrastructure to identify fungal pathogens.
5. Why the repository exists: PGIMER began storing fungal pathogens some 25 years ago and now holds 15,000 clinical fungal isolates from across India, helping other centres identify and culture them free of cost.

What did the study find about resistance in Indian isolates?

1. Azole resistance is near universal: More than 90 per cent of clinical isolates of C. auris are resistant to common azole based antifungals such as fluconazole.
2. Polyene resistance is substantial: About 30 per cent of the isolates are resistant to the polyene class, leaving the echinocandins as the class they mostly still respond to.
3. What the drugs target: Azoles and polyenes target ergosterol, a fat enriched in the fungal cell membrane, while echinocandins target the cell wall outside it.
4. Gene amplification defeats azoles: Grown in the presence of fluconazole, the pathogen makes extra copies of the Erg1 gene, which raises ergosterol production and cancels the drug’s effect, and the study located genome regions carrying those additional copies.
5. Mutation defeats echinocandins: With echinocandin drugs such as caspofungin, the team found mutations in the Fks1 gene that allow the pathogen to resist the drug’s action, along with genetic changes promoting higher tolerance.

Why do current susceptibility tests understate the problem?

1. The survival ceiling is higher than the test: Fks1 mutations can enable C. auris to survive caspofungin doses up to 16 micrograms per millilitre, so a patient carrying such a pathogen needs a concentration above that.
2. The test stops well short: Clinicians test the pathogen’s ability to survive only up to 2 micrograms per millilitre of caspofungin, as defined by the U.S. Centers for Disease Control and Prevention and followed globally.
3. The clinician cannot see the resistance: A pathogen surviving eight times the tested concentration is reported as manageable, so the dose chosen is set by a number the organism has already passed.
4. Why genotyping is not the practical answer: Looking for mutations such as those in Fks1 is the logical route, and the associated costs make raising the susceptibility test ceiling above 16 micrograms per millilitre the workable step.

Why does a higher dose sometimes fail outright?

1. The paradox: C. auris carrying no specific gene mutation or duplication still dies at lower concentrations of caspofungin and survives at exceptionally high ones.
2. Compensatory pathways switch on: Caspofungin at high doses activates compensatory pathways in the fungus rather than killing it.
3. Chitin rebuilds the wall: The fungus starts producing chitin, the raw material of the fungal cell wall, in large quantities, so damage the drug causes to the wall is compensated and the wall stays intact.
4. The named phenomenon: Such cases of paradoxical growth are called the Eagle effect, after the U.S. pathologist Harry Eagle.

Why are scientists rethinking the arms race approach?

1. Evolution answers every lethal target: Targeting a molecule without which an organism cannot live guarantees that its population survives with a changed molecule, which is the mechanism the arms race keeps re running.
2. Disarm rather than kill: The alternative is to target less critical molecular pathways whose inhibition lets the pathogen survive without causing disease, which removes the selective pressure driving resistance.
3. Combination therapy in the interim: Combining therapies to target cellular compensatory pathways would keep the major antifungals effective against drug tolerant species.
4. Testing has to change first: The findings make more nuanced susceptibility testing the precondition for setting any antifungal dose correctly.
5. Two routes to protection, not one: Fungi are protected from antifungals by genetic mutations and by making more copies of protective genes, so a strategy built against mutation alone is incomplete.

Challenges to controlling antifungal resistance in India

1. The drug arsenal is narrow: Only three classes are in wide clinical use, so resistance in one class removes a third of the available treatment at once. Eg. Isolates resistant to azoles and polyenes leave the echinocandins as effectively the only remaining option.
   The Fix: Fund antifungal discovery through the push and pull incentive model used for new antibiotics, since the commercial return alone will not carry it.
2. Agricultural fungicide use drives clinical resistance: Fungicides chemically related to clinical azoles are applied to crops, selecting for resistance in the environment before any patient is treated. Eg. Azole resistant Aspergillus fumigatus in Europe has been traced to agricultural azole fungicide use.
   The Fix: Adopt a One Health framework linking crop fungicide approvals to clinical resistance surveillance, so an agricultural licence accounts for its medical cost.
3. Surveillance is built around bacteria: National antimicrobial resistance monitoring covers bacterial pathogens far more completely than fungal ones, so fungal resistance trends stay invisible to policy. Eg. India’s National Action Plan on Antimicrobial Resistance and the surveillance networks under it report predominantly bacterial isolates.
   The Fix: Make a laboratory confirmed C. auris finding notifiable, with mandatory reporting into the national resistance surveillance network.
4. The pathogen persists in hospital environments: C. auris survives on surfaces, bedding and medical devices and resists several routine disinfectants, so an intensive care unit reinfects itself. Eg. The U.S. Centers for Disease Control and Prevention classifies C. auris as an urgent threat requiring specific disinfection protocols.
   The Fix: Mandate contact precautions, dedicated decontamination protocols and patient cohorting in intensive care units wherever the pathogen is confirmed.

Conclusion

The study’s practical output is narrow and immediately actionable. Raising the caspofungin susceptibility ceiling used in Indian laboratories costs almost nothing and would stop clinicians prescribing against a number the pathogen has already outgrown. The larger claim is harder, because abandoning the arms race means accepting drugs that leave the pathogen alive and only stop it causing disease, which is a different standard of success from the one antimicrobial development has used so far. Whether Indian laboratories revise their testing ceilings is the near term marker of whether the finding changes practice.

Matching Previous Year Question

“[2019] Which of the following are the reasons for the occurrence of multi-drug resistance in microbial pathogens in India? 1. Genetic predisposition of some people 2. Taking incorrect doses of antibiotics to cure diseases 3. Using antibiotics in livestock farming 4. Multiple chronic diseases in some people Select the correct answer using the code given below. (a) 1 and 2 (b) 2 and 3 only (c) e) 1, 3 and 4 (d) 2, 3 and 4 Answer: (b)”