High time to tackle drug-resistant fungal infections | Hacker News Reader

High time to tackle drug-resistant fungal infections

nature.com

137 pointspmags45 comments

//Thermotolerance Adaptation// The main reason why fungal infections typically kill only elderly and sick humans (mammals) is body temperature. Most fungi cannot survive at human body temperature (~37°C). Rising global temperatures are driving fungi to adapt by becoming more thermotolerant, enabling them to survive and replicate at human body temperatures.

Effects of climate change on fungal infections https://journals.plos.org/plospathogens/article?id=10.1371%2...

Zoonotic Risk from other mammals to humans will increase similarly. Pigs, cows or poultry might become spread the adaptions and then spread them to humans.

The last of us are going to know how dangerous this is

"Rising global temperatures are driving fungi to adapt by becoming more thermotolerant..."

Your link only mentions Candida auris. I do not find it compelling to blame this on recent global warming for two reasons: 1) Regional and seasonal temperature variation is much greater than global variation and therefore the first place to look for temperature-specific adaptation, 2) The presence of an adaptation to the human body temperature in a human pathogen is not exactly remarkable or new.

The thing about Candida auris is not that it is heat-resistant, but that it is drug resistant. IMO, it's worth looking at the evidence that the appearance of Candida auris is related to the use of agricultural antifungals in East Asian agricultural production.

> appearance of Candida auris is related to the use of agricultural antifungals in East Asian agricultural production

Can you elaborate on share documents on this? I’m wondering why east asia is different in anti fungal usage.

"Can you elaborate on share documents on this?"

https://archive.is/uTAaW

"I’m wondering why east asia is different in anti fungal usage."

It is a logical error to assume that it has to be substantially different. East Asia is simply the region that Candida auris originates from (ie., evolved in). It was first noticed in Tokyo and South Korea, and eventually India a few years later.

EDIT:

Actually, looks like there's some evidence that multiple evolutionarily-separate unrelated strains attained drug resistance one after another. Presumably the same antifungal agricultural product would have been in widespread use if this is the cause. If you look at the PLOS article linked in the NYT article in my link, they give an example of this for Aspergillus fumigatus strains.

[1] https://journals.plos.org/plospathogens/article?id=10.1371/j...

I too think that we don't yet have convincing evidence that recent changes in global temperature have driven thermal tolerance. However, there are some interesting aspect of C. auris that are worth pointing out:

• C. auris does have unusual thermotolerance -- it grows up to 42C which is unusual compared to other Candida species.

• C. auris does not appear to be a typical commensal of mammals, or other high body temp animals, and hence it's thermal tolerance is likely not due to selection for this aspect of the host niche

Some more info on C. auris and hypotheses about origins here:

• Sharma C, Kadosh D. Perspective on the origin, resistance, and spread of the emerging human fungal pathogen Candida auris. PLoS Pathog. 2023 Mar 23;19(3):e1011190. doi: 10.1371/journal.ppat.1011190. PMID: 36952448; PMCID: PMC10035752.

But I agree

There are at least some cases where fungi can cause illness in otherwise healthy humans.

The one that comes to mind is ergot, by ingestion of a chemical byproduct:

https://en.m.wikipedia.org/wiki/Ergot

A number of poisonous substances in mushrooms are reviewed in this wiki:

https://en.m.wikipedia.org/wiki/Mushroom_poisoning

I also checked "black mold," but it appears that link is not firmly established:

https://en.m.wikipedia.org/wiki/Stachybotrys_chartarum

Fungal pneumonia is well-known, but apparently not prevalent beyond the immunocompromised:

https://en.m.wikipedia.org/wiki/Fungal_pneumonia

From the editorial in Nature:

Around 3.8 million people die each year of infections caused by C. auris and other fungi. Annual deaths caused by fungal infections have nearly doubled in the past decade.

Pathogenic fungi pose unique challenges, and overcoming them will require innovative approaches to both science and policy. Yet, despite the growing global threat posed by drug-resistant fungi, such infections rarely loom large in discussions of antimicrobial resistance. Two World Health Organization (WHO) reports published this month (see go.nature.com/3rniybw) — the organization’s first analyses of tests and treatments for fungal infections — highlight the result of that neglect.

Looks like this could affect how we grow crops, maybe pish for more different techniques to avoid pesticides, and also lead to new life habits.

I hope WHO or some group of researchers somewhere will start studying how to tackle these fungi infections. Given the current situation of global conflicts, political situation, and economy around the world, if these infections become more widespread and resistent if could be devastating.

Pesticides have nothing to do with this. Staple crops in the United States essentially do not use fungicides anymore. GM crops have negated that need.

Edit: what did I say that was incorrect?

n.b. Down votes are not mine

Azoles (and other antifungals) are indeed still used in the US and there is documented azole resistance in important opportunistic fungal pathogens such as Aspergillus in the US:

• Celia-Sanchez BN, Mangum B, Gómez Londoño LF, Wang C, Shuman B, Brewer MT, Momany M. Pan-azole- and multi-fungicide-resistant Aspergillus fumigatus is widespread in the United States. Appl Environ Microbiol. 2024 Apr 17;90(4):e0178223. doi: 10.1128/aem.01782-23. Epub 2024 Apr 1. PMID: 38557086; PMCID: PMC11022549. -- https://pmc.ncbi.nlm.nih.gov/articles/PMC11022549/

Table 1 in this paper gives estimated azole use in various countries. US is lower than many European nations but still nowhere near zero.

• Burks C, Darby A, Gómez Londoño L, Momany M, Brewer MT. Azole-resistant Aspergillus fumigatus in the environment: Identifying key reservoirs and hotspots of antifungal resistance. PLoS Pathog. 2021 Jul 29;17(7):e1009711. doi: 10.1371/journal.ppat.1009711. PMID: 34324607; PMCID: PMC8321103. -- https://pmc.ncbi.nlm.nih.gov/articles/PMC8321103/

The GP mentions "staple crops". In the US, azoles are used more on corn, wheat and soybean seeds than they are the actual crops themselves. Rice, on the other hand, and others get direct applications to the crops.

Presumably, applying it to the seeds going into storage is safer than applying in the open environment, but it's probably redundant since the Google claims azole use in the US is increasing.

Correct. There is a difference between seed treatment and broadcast treatment of crops.

Practically, there's no way to stop anti-microbial resistance. We've only been capable of using said drugs for an x number of years because of the relatively long time it takes for these resistant spores to become dominant in most soil around the planet. The problem isn't really the development of resistance itself but our way of farming is the perfect petri-dish for fungal and bacterial evoluton. E.G. large monocrop fields with single-use anti-fungal spray and rinse.

Found the „it can’t be done” guy.

At least its now out in the open.

Found the German, can vs. should matters.

Save this criticism for the people who aren't nuanced, they left avenues. Mitigation, not eradication.

Before you take this personally, I'm talking about the quotes. Not history.

edit: downvoters and I would also disagree RE: Sisyphus. The punishment is worth it, bro. /s

I upvoted you in lieu of an olive branch.

Points all around, this is more in jest than text generally allows

I don't think that's right.

* There is limited evidence that farming use of antibiotics is what drives resistance in clinical cases. That is - we use enormous amounts of antibiotics in farming, but the resistance it creates doesn't really seem to move into the hospitals.

* There is no reason to believe we've hit a wall and can't invent more antibiotics in the future. Historically we haven't focused much on antibiotics because we already have a bunch, and because there is less money in developing those drugs compared to e.g. lifestyle drugs or chemotherapy.

* We can still adopt better policies in the future to fight against resistance. For example, some countries crazily overprescribe antibiotics, or prescribe broad spectrum ones. We can also still amp up hygiene in hospitals - literally paying more people to scrub and boil and sterilize stuff will work.

* There are still some antimicrobial treatment techniques we haven't put a lot of resources in. Like, bacteriophage treatments, or cycling antibiotics.

> There is no reason to believe we've hit a wall and can't invent more antibiotics in the future

That just kicks the can down the road though. Assuming that the use of any antibiotic will eventually lead to a predominance of resistance, we would have to continue to invent new, effective antibiotics indefinitely.

> For example, some countries crazily overprescribe antibiotics, or prescribe broad spectrum ones

I don't think its as simple as over prescription being the problem. My grandmother is pretty I'll these days, she suffers from dementia, is sick frequently, and generally just very warn down. She had a respiratory infection this week and while at the doctor they also found that she has a UTI. The prescribed her two different, non-broad spectrum antibiotics.

I don't think anyone would consider that over prescribing, and she likely would have a very bad outcome without it, but it also seems totally reasonable that her scenario could still lead to antibiotic resistance. Her immune system just doesn't work well anymore, the antibiotics will take out most of the infection and her symptoms will likely go away but I wouldn't expect her body to do the job of cleaning up the rest of the infection, leaving the more resistant strains around in her system.

We don’t have to keep creating new antibiotics indefinitely. There’s always some cost to resistance. Once a drug is no longer present in an environment, non-resistant strains tend to outcompete resistant ones. That is if you just stop using an antibiotic, bacteria will tend to lose resistance to it.

Theoretically once you have enough antibiotics that we can retire drugs with heavy resistance and keep cycling them, you won’t need to keep creating new antibiotics.

There's a lot baked into that theory (well, hypothesis) though. We haven't gone through a cycle like that yet that I'm aware of, moving back to an old antibiotic because the newer one is no longer effective.

Looking just at the evolution of it, there would need to be pressure to actively select against the learned resistance. Maybe it would be lost eventually, but we couldn't rely on that unless something pushed the bacteria away from it rather learning to resist the new antibiotic in addition to the old one.

This has been well researched. Most antibiotic resistance has a fitness cost. Which means the resistance is being actively selected against.

This isn’t always the case. There are some adaptations that don’t have an observable fitness cost, but the majority do. That is, in a lab when you remove the antibiotic, we observed that the number of resistant bacteria drops over time.

We have also observed this in the real world. When we reduce usage of a specific antibiotic. The percentage of resistant bacteria in the wild drops.

The question is how long you’d have to retire an antibiotic and how many different antibiotics you’d need for this strategy to be viable.

Sure, but I think we agree then. What you describe is a hypothesis based on a few important assumptions. For example, that controlled lab studies are predictive analogs for the natural world, that a drop in resistance in such a controlled study will match a real world scenario, and that the rate at which resistance is lost can reasonably be matched by cycling in different drugs.

I'm not saying it isn't possible, maybe it is! Only that its a hypothesis and that the key assumptions are still just that rather than known parameters.

We have more than lab studies, we have real world observations that show the percentage of resistant strains dropping when we reduce the use of a specific antibiotic.

We may not be able to produce new antibiotics fast enough to get to the point where we have enough to cycle them effectively. That’s entirely possible.

But we have very good evidence that there is a point at which we would have enough. I mean at the limit there is a maximum amount of information bacteria can store in their genes, so there certainly exists some maximum number of resistances they can retain.

My point isn’t that we’re going to have enough to do this in x years. My point is that while we don’t know how many different antibiotics we need, we are almost certain that that number isn’t infinite.

Everything that reproduces is in an evolutionary arms race (https://en.wikipedia.org/wiki/Evolutionary_arms_race), so the "kicking the can" objection doesn't really make sense in this context.

There is no alternative to inventing new weapons continuously. We are simply used to winning without much effort since Fleming found penicillin, a naturally occurring fungal compound. Previous successes have limited the economics of continuing to develop new solutions, which is contributes to the uptick in resistance.

This doesn't mean we shouldn't be judicious in the tradeoffs that we choose and try to avoid a purely chemical solution to the arms race. For example, as robotics get better, we should move away from mono-cropping toward combinations of plants that naturally ward off pests. There are better ways to stay ahead than blunt tools.

>There is limited evidence that farming use of antibiotics is what drives resistance in clinical cases.

This is a classic example of asymptotic behaviour analysis.

>That is - we use enormous amounts of antibiotics in farming

You're entirely correct, the data fits an almost exponential curve, the only limiting factor so far has been soil health and costs. the amount of biocides we have to use to keep our productivity will be impossible to match and therefore, even with 0 transference of resistance to human antibiotics, you're gonna see more transference to humans because of farming-biocide resistance. ofcourse, most of this will result in lower crop yield instead of actually selling bad product, this can be slowed down with essentially the same policies and techniques as hospitals employ. But the core problem is the exact same, the extremely quick and deadly takeover of a single strain resistent against our current quo pro due to overuse of a single line of defence.

I agree that there is still a lot we can do to combat fungal disease.

However, your points 1, 2, and 4 unfortunately don't apply well to anti-fungals.

* "There is limited evidence that farming use of [anti-fungals] is what drives resistance in clinical cases."

Certainly not the case with respect to azoles:

-- Rhodes J, et al. Population genomics confirms acquisition of drug-resistant Aspergillus fumigatus infection by humans from the environment. Nat Microbiol. 2022 May;7(5):663-674. doi: 10.1038/s41564-022-01091-2. Epub 2022 Apr 25. Erratum in: Nat Microbiol. 2022 Nov;7(11):1944. doi: 10.1038/s41564-022-01160-6. PMID: 35469019; PMCID: PMC9064804. https://pubmed.ncbi.nlm.nih.gov/35469019/

-- Celia-Sanchez BN, Mangum B, Gómez Londoño LF, Wang C, Shuman B, Brewer MT, Momany M. Pan-azole- and multi-fungicide-resistant Aspergillus fumigatus is widespread in the United States. Appl Environ Microbiol. 2024 Apr 17;90(4):e0178223. doi: 10.1128/aem.01782-23. Epub 2024 Apr 1. PMID: 38557086; PMCID: PMC11022549.

-- Impact of the use of azole fungicides, other than as human medicines, on the development of azole‐resistant Aspergillus spp. https://www.efsa.europa.eu/en/efsajournal/pub/9200

"* There is no reason to believe we've hit a wall and can't invent more antibiotics in the future. "

-- There are very few anti-fungals, because fungi, being eukaryotes, have cell biology so close to ours. The "big three" are 1) azoles (lots of resistance; see above); 2) echinocandins; and 3) amphotericin B (highly toxic to the host)

-- One bright spot is a new antifungal published a few weeks ago in Nature, called Mandimycin: https://www.nature.com/articles/d41586-025-00801-0

* "There are still some antimicrobial treatment techniques we haven't put a lot of resources in. Like, bacteriophage treatments, or cycling antibiotics."

-- Bacteriophage don't work on fungi. Some degree of cycling and combination anti-fungal treatment are already in use.

#proudinvestor (very early angel) in Amplyx pharmaceuticals (fosmanogepix) from many years ago.

fosmanogepix has proven anti-fungal activity in 4 of the 5 target classes and is in stage III trials.

https://pmc.ncbi.nlm.nih.gov/articles/PMC11131969/

https://www.google.com/search?q=amplyx+pharmaceuticals

https://www.google.com/search?q=Fosmanogepix

The cure for most drug-resistant fungal infections is simple:

There are 3 common anti-fungals: clotrimazole, miconazole, and tolnaftate.

For external fungal infections (e.g. toe fungus,) the area can be kept dry if you use powdered anti-fungals.

For internal fungal infections (e.g., vaginal infections) is is not possible to keep the area dry, so don't try to keep it dry.

The cure is to rotate among the 3 common anti-fungals and keep the area dry if possible.

The first problem is that, most people in the USA do not know that powdered clotrimazole is available by prescription.

The second problem is that this course of treatment is illegal in the USA. US law prohibits doctors from advising patients to take OTC meds (powdered miconazole and tolnaftate) with prescription meds (powdered clotrimazole.) Doctors literally spend years advising their patients on methods they know will not cure their infections, because it is illegal in the USA to explain what will cure it.

> Between 30% and 60% of the people it infects will die.

I assume there's an implicit "within x amount of time" here?

In the study I'm aware of, 18 patients became infected in hospital and there was a 28% death rate within 30 days [0]

[0] https://www.journalofinfection.com/article/S0163-4453(16)301...

Surgery is a real threat to get a potentially deadly fungal infection internally. Where are the options for treatment?

What would it take to create the “mRNA moment” for antifungal drugs—something that accelerates both funding and discovery at scale? Are there promising platforms (e.g. AI drug discovery, CRISPR screening, biofoundries) that could shift the economics of developing treatments for rare but rising fungal threats?

I’m an outsider to that field, but I don’t see a reason why mRNA can’t be the “mRNA moment” - fungal vaccines are possible, and if you can find the right target protein you can make an mRNA vaccine against a particular infection.

I think it’s just a matter of priorities and funding, which fungal infections as a whole don’t get enough of in general.

What precisely is the suggested mechanism by which agricultural anfifungals affect human pathogens?

Is it just that they select resistant fungi and we eat that?

Or is it that we eat leftover azoles and thus build up immunity?

Only fungal? What about funguy?

What about letting a more innofensive variant spread? You know, not cleaning stuff just because it is slightly moldy (doesn't mean eating it!).

It would be hilarious if cleaning is actually what selects the strongest bacteria and funghi to thrive. I mean tragic, not hilarious.

But I'm no biologist. I have only mediocre high school understanding of such things.

ummmm, hmmmmmmm, It's high time we realised that we are the largest single niche, and animal biomass, that possibly, has ever existed, and it is a law of biology, that each niche will be filled. This means that any peicemeal approach is going to lagg, and uncontrollable epidemics become more and more likely. Confounding factors are that our diets and lifestyles are converging into a more homegenous whole, and all in all we live longer, but are less fit ,while dependent on our haphazard use of "medicine" to provide cheap health care. My personal experience is that I now notice a lot more fungal smell in otherwise good looking food, and have stopped buying certain foods, not that I worryed about catching anything, but that it tastes bad, and is alarming only because it is a "stealth" fungus, often showing as just a tiny bit of black stuff, rather than an obvious fuzzy mess.

Humans aren’t the largest biomass

Relevant paper: The biomass distribution on Earth

https://www.pnas.org/doi/10.1073/pnas.1711842115

I saw a good 3D visualization of this data using a customized version of Minecraft:

https://www.youtube.com/watch?v=hXDZ2LTTKUE&t=505s

Yeah, that sounded wrong to me. We punch pretty high for a single species though:

https://www.weforum.org/stories/2021/08/total-biomass-weight...

"By weight, human beings are insignificant."

https://www.vox.com/science-and-health/2018/5/29/17386112/al...

(Sorry you're getting down voted.)

diferent sources put humans as second only to cattle, for a single animal species, so I was wrong, but I did mean single species of animal. As to getting down/up voted, I am useing it as an anylitical tool to understand what facets of what I write are offensive, at least to some, and a fine line seems to exist where some of what I say, gets positive comments, or engagement, while bieng down voted at the same time, which is puzzling but interesting.If I go through what I write a few times, sometimes I can see the possibly ambiguous bits, and make them clearer, which seems to lessen the down voteing. Kind of like a tough love writing school around here that way.

A few decades from now people will discover that drugs are not the right way to kill fungal infections.

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