Tweetorial: Antifungal Agents

18 March 2023

Mar 18, 2023

Winter seems to have put me in a mood to talk about anti-infective agents. Having personally gone through both COVID and flu in the space of a month back in January, this naturally led to some posts on drugs for those particular viruses. The antiviral pharmacopeia there isn’t huge, and pound-for-pound other viruses like HIV have many more drugs in the arsenal. Viruses are harder to drug, on average, than bacteria — indeed we’ve had a golden century of antibacterials. It’s difficult to fathom that in just five more years (2028), we’ll have reached a full 100 years since Fleming’s isolation of penicillin.

Antibacterials have become so engrained in daily life — much like vaccines — that we struggle to imagine a world without them. We have a short collective memory, though, regarding the toll childhood illnesses used to take. In 1800, US under-5 child mortality was ~462 per thousand. Basically your chances of making it to age 5 were a coin toss. By 1930, improvements in sanitation and modern medicine had reduced that number to ~102 per thousand. That’s >4x lower since 1800, but think about it this way: in 1930, if you had a group of 30 kids in a small town born around the same time who would end up going to school together, 3 of them weren’t going to make it to kindergarten.

We’re only talking a handful of generations ago that this was reality — my grandparents’ generation, or perhaps your great-grandparents’. That kind of mortality is unthinkable today, when further improvements in medicine, including antibiotics and vaccines, have pushed under-5 child mortality to 7 per thousand as of 2020 — 14x lower than 1930 and 66x lower than 1800.

This collective memory loss is what makes scientists shudder. Vaccines in particular have been so effective in reducing the burden of childhood disease that we forget many of these diseases (smallpox perhaps excepted) continue to linger in reservoirs and now routinely break through where we’ve willfully allowed our herd immunity to break down. Today we sit around and debate the merits of immunity from infection vs. intervention with vaccination or pharmaceuticals. While there’s little doubt in my mind that immunity from infection does indeed in many cases confer excellent immune protection, you first have to survive to gain said protection. The childhood mortality stats don’t lie. Kids back in the day got immunity from infection to a host of diseases because it was the only option — but they also died. A lot.

Central to the premise of both vaccines and anti-infective pharmaceutical agents is the ability to distinguish self (our bodies) from other (the pathogen). Viruses are way removed from us; they don’t appear on our phylogenetic tree because there are no shared common ancestor genes with either cellular organisms or really even other viruses. Indeed, we continue to argue about whether or not they’re even properly considered “alive”. Finding a drug with selectivity for a viral target over the host is thus comparatively easy. The challenge is finding and drugging the viral target in the first place. The viral genome is small relative to a bacterial or human genome — and therefore the number of potential targets to drug are few. Viruses are laser-focused on cellular entry and replication, with just enough structural proteins to keep it all packaged together. Compare SARS-CoV-2 with its 11 genes and ~29 coded proteins vs. 4,401 genes in an E. coli bacteria and 20-25,000 genes in humans. Slim pickings for the viruses, which is perhaps why we’ve had more luck with vaccines there.

Bacteria, as prokaryotes, have enough phylogenetic distance from us eukaryotes that numerous druggable targets have been identified over the years. We have many classes of antibacterials today, but over/misuse is leading to rapid resistance. In 2013, the CDC estimated there were >2M antibiotic-resistant infections in the United States, leading to >23K deaths. (Note this total includes bacterial + fungal infections together, but not viral.)

Which brings us at last to the fungi. If you look at the phylogenetic tree of cellular organisms, fungi are our nearest neighbors. Their genome size is generally intermediate between animals and bacteria and most similar to animals. Drugging fungi is thus a miserable endeavor. We have little on the pharmaceutical shelf, rising resistance to the drugs we do have, and no vaccines.

So it was only a bit of a stretch for the folks who designed the video game The Last of Us to contemplate a dark horse pandemic — not the viral one that we’ve lived for the last few years, nor the future viral ones we fear, but a fungal one. There are a number of implausible things that would have to happen for a fungus to jump to a new host (us) and spread so rapidly, so: not impossible (except maybe the turning-us-into-fast-zombies part), just very improbable. Now that the game has been made into a hit TV series on HBO, I hope that the science community can use it to do some good and raise awareness (and funding) for more research and development on antifungals. It’s badly needed.

Without further ado:

Tweetorial: Antifungal Agents

18 March 2023

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