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Pyridomycin: nature's isoniazid
September 21, 2012 2:52 AM   Subscribe

Drug-resistant and "extensively" resistant strains make containment and treatment of tuberculosis ever more difficult. Fortunately, researchers based in Switzerland have (re-)discovered a naturally-made antibiotic called pyridomycin, which will kill isoniazid-resistant M. tuberculosis bacteria.
posted by Blazecock Pileon (31 comments total) 19 users marked this as a favorite

 
This looks like exciting new research and reading through the actual paper, by the way thanks for linking to it, they’ve found some really cool things. However, there is a lot of stuff they still need to do to show that it will be actually useful. To understand them will require a little bit of background on what makes antibiotics so awesome,

Antibiotics are so useful because they are compounds that are more toxic to the bacteria attacking us then they are to us. For example, while bleach is really really effective at being toxic to bacteria, it would not be a good antibiotic because it is also pretty darn toxic to us. In a very rough sense, how good an antibiotic is depends on its effectiveness, as generally abstracted by its Minimum Inhibitory Concentration (MIC) or the lowest concentration of the stuff necessary to stop the growth of the bacteria in question, versus its toxicity to us measured in approximate LD50, or the concentration that is likely to kill half your patients. Antibiotics are able to be differently toxic by taking advantage of differences between bacteria and us, and there are indeed depressingly few. These days, most antibiotics work by taking advantage of the fact that bacterial ribosomes are pretty different from ours and work by acting as a monkey wrench that fucks up theirs but doesn’t fit into ours. Membrane synthesis also works pretty differently and so many others work by fucking up some aspect of making new membranes that bacteria have but we don’t. There are also some pretty neat antibiotics that target things like differences in DNA synthesis, central metabolism, and a few others.

In this case, the Swiss based researchers have figured out how an old drug, that was set aside back in the 50s, works. It takes advantage of a difference in the synthesis of cell membranes between us and mycobacteria. Specifically, mycobacteria have a waxy outer layer of their membranes called mycolic acid (If you ever want to watch a room of microbiologists get shouty just ask everyone whether that layer is a second membrane or not) that we don’t have. Thus their pathway for making fatty acids (the components of lipid membranes) has to be different from ours in order to make the different kind of fatty acid. The authors have figured out that this old drug targets InhA (which they really should be calling FabI), an essential component of the type II fatty acid synthase system (FasII) involved in fatty acid elongation and is required for mycolate production in M. tuberculosis. This is good news for them because FabI is an essential part of fatty acid biosynthesis meaning that it will be hard to generate resistance against by just losing the enzyme, the mycobacterial FabI is pretty different from that of other bacteria (which is why they have their own name for it) meaning that they won’t be generating resistance to it in other bacteria or harming helpful bacteria, and InhA is really conserved in M. tuberculosis meaning that it will be broadly effective. The interesting news is that other antibiotics that already target InhA have already been found, and resistance to them doesn’t confer resistance to Pyridomycin. The bad news is that they also already found a strain that is resistant to Pyridomycin.

In their paper the authors show that when they manipulate a strain of M. tuberculosis to express FUCK TONS of the InhA, that strain manages to get pretty fucked up by it, but gains some measurable resistance. While this wouldn’t really be a very viable strategy in the wild, it does demonstrate that InhA is the target. Similarly they show that Pyridomycin has a pretty low MIC, meaning that it doesn’t take much of the drug to be really deadly to M. tuberculosis, which is a really good thing. They also took the time to show that its not that toxic to human cell lines, which is an indication of the work they have left to do to make a reasonable drug. Human cell lines are reasonably indicative of how people will respond to something, and you can kill as many as you like to figure out just exactly how much of a substance you need to kill them - which is useful - but they aren’t people. To demonstrate safety and efficacy, the researchers will need to find a company willing to invest fuck tons of money into getting healthy volunteers to try it out and see if it kills them (Phase I trial), then get a bunch of sick people to try it out (Phase II trial), and then get A LOT of sick people to try it out (Phase III trial). This will also test to see if there are any unpredictable fucked up things that would happen to safety like drug interactions or a really specific toxicity to pancreas cells or whatever, or unpredictable stupid things that would happen to efficacy like a human enzyme that just phosphorylates it somehow and tags it to get pissed out really quickly or something.

One of the neatest parts of the paper is that while they did find a mutation in the InhA target that generated resistance to Pyridomycin, it is a fundamentally different kind of mutation than other mutations in InhA that generate resistance to other drugs that are already used. This indicates that that there are fundamentally different was to fuck up InhA in wild strains infecting people; meaning that if we use each of the drugs that fuck up InhA together, then that might be more difficult to generate resistance against - maybe. Either way its pretty cool.
posted by Blasdelb at 4:40 AM on September 21, 2012 [40 favorites]


Also, I can't really tell whether its freely accessible from here but if anyone would like a PDF, for the purposes of this academic discussion that we are currently having with each other, just memail me with an email address I can send it to. The crystal structure in Figure 5 is very pretty.
posted by Blasdelb at 4:51 AM on September 21, 2012


God help me, but it's early and I'm eating a breakfast burrito, and at first I read this as "containment and treatment of hermitosis" and I was all THAT IS AN OUTRAGE, HE IS PRETTY GREAT
posted by Madamina at 5:06 AM on September 21, 2012 [3 favorites]


While this is good news it's almost like there's this invisible force that is creating new resistant bacteria even as we come up with treatments for the old ones. The only thing that's prevented the evolution of bacteria resistant to this is the fact that we haven't been using it.
posted by Kid Charlemagne at 5:09 AM on September 21, 2012 [1 favorite]


If they're careful using it, resistance can be avoided.

But they won't be. It'll be abused just like the others were, and in 20 years it'll be useless too.
posted by Chocolate Pickle at 5:20 AM on September 21, 2012


But most M.tb resistant to INH is also resistant to rifampicin, which serves an entirely different purpose than INH in terms of killing off waxy old M.tb. And that's just for starters - for extensively drug-resistant TB (XDR-TB), there's resistance to additional second-line drugs. So: cool, but there are also a decent amount of regimens - both novel compounds in the sense that they use new drugs with drugs we already use (like pyrazidimide), and novel regimens that use only new drugs - that are much farther along. The moxifloxacin-containing regimens, for example, are in phase III, and they theoretically work for both drug-sensitive and drug-resistant TB in places where flouroquinolines aren't over-the-counter / there's not a ton of resistance.

So: cool, but not particularly ground-breaking.
posted by quadrilaterals at 5:50 AM on September 21, 2012


Also, TB becomes resistant for really dumb yet complicated reasons. Like, Country X doesn't buy TB drugs that work; they instead have a corrupt system that buys all of the country's drugs from shitty manufacturers. The bacteria get used to a small amount of the active ingredient, and then they're resistant. In Country Y, there's just not enough doctors/nurses/whoever asking people if they've been coughing for more than two weeks, and if they've had night sweats / fever. In Country Z, people get TB in prison, where they get some treatment, but once they're released, treatment stops.

Add to this that TB hasn't had any new drugs developed in fifty years, and of course we have very drug-resistant strains floating around. Two fucking billion people have TB (in that they would show positive in one of those skin tests most Americans get before school), but most of them don't get sick. A lot of people do get sick, though; in fact, one in four HIV deaths is caused by TB.

Anyway, on drug resistance, most of my colleagues don't believe that there is such a thing as totally drug-resistant TB, that it's just poorly managed XDR-TB. That's not particularly reassuring, but it is something.
posted by quadrilaterals at 5:55 AM on September 21, 2012 [2 favorites]


Also, TB becomes resistant for really dumb yet complicated reasons

And, as you know, Bob,* TB is really good at becoming resistant. ISTR that 1 out of every 107 bacterium in normal TB is resistant to ethambutol, and one in every 1012 is resistant to rifampicin. So, a typical DR TB case has some 100 rifampicin and 10000 ethambutol resistant bacteria at all times.

Thus, the multidrug treatment, since the chance of being naturally resistant to ethambutol, rifampicin, steptomycin and isoniazid is astronomically high -- some 1 in 1033.

I hope you and your colleagues are truly right about the lack of TDR-TB in the world.


* This is an old jokey SF convention, coming from the highly trained starship engineer telling the highly trained captain some basic fact about starships that even the rawest recruit in the star fleet would know, but the reader does not.
posted by eriko at 6:24 AM on September 21, 2012


And, as you know, Bob, TB is really good at becoming resistant.

TB is just a really strong, waxy bug in general. That's a big issue in disease advocacy - so malaria and HIV communities get to say, "oh, let's eliminate this!" But TB doctors/scientists are very doctor-y/science-y, and spend lots of meetings insisting that we will never eliminate TB, and thus the community ought rally around a cry of "a 15% reduction of death and DALYs due to..." and: no. That doesn't work. TB should be something we can reduce, and make it so that people have access to affordable, appropriate treatment. But there's really not enough dollars in the game to make it happen, and it's hard when you can't translate things from scientist to real-person talk. It's even harder because the community isn't quite sure that they want to make that happen.

(Compared to my colleagues and most people I'm around all day, I know virtually nothing about TB and make mistakes talking about it all the time. But as my knowledge about TB prior to this job came from Crime & Punishment, I think I'm doing pretty well. I can certainly confuse the hell out of my non-TB friends.)
posted by quadrilaterals at 7:29 AM on September 21, 2012


Queue the zombies in 3... 2...
posted by bpm140 at 7:40 AM on September 21, 2012


If they're careful using it, resistance can be avoided.

But they won't be. It'll be abused just like the others were, and in 20 years it'll be useless too.


Cue commercial that implies if you really care about your family you'll use CloroxTM brand disposable kitchen wipes (now with pyridomycinTM)...
posted by The 10th Regiment of Foot at 7:58 AM on September 21, 2012 [2 favorites]


The first farmer who tries to feed this drug to his cattle should be lynched.

Pour encourager les autres.
posted by ocschwar at 8:00 AM on September 21, 2012 [1 favorite]


Very cool, thanks for posting this, Blazecock.

Blasdelb: "Specifically, mycobacteria have a waxy outer layer of their membranes called mycolic acid (If you ever want to watch a room of microbiologists get shouty just ask everyone whether that layer is a second membrane or not) that we don’t have."

Seems to me that the mycolic acid should be considered part of the cell wall since it is covalently linked thereto. Here's a figure from that review showing the structure.
posted by exogenous at 8:12 AM on September 21, 2012


at first I read this as "containment and treatment of hermitosis" and I was all THAT IS AN OUTRAGE, HE IS PRETTY GREAT

Agreed, but you have to admit, his growing drug resistance is worrisome.
posted by infinitywaltz at 8:45 AM on September 21, 2012 [2 favorites]


Blasdelb summed it up pretty well. You may note the authors make a big deal about the drug being active intracellularly and that will also make a big difference as to whether it is helpful or not. I'm not convinced it will get to the tubercular organism in human macrophages. It is a relatively large molecule (MW 540 vs. isoniazid 137). Big molecules generally don't penetrate human cells well. Another drug to attack extracellular TB is not going to help much.



Other major players against intracellular TB:

ethambutol MW 277
pyrazinamide MW 123

On the other hand:
rifampin MW 822.
posted by dances_with_sneetches at 9:02 AM on September 21, 2012 [1 favorite]


> The interesting news is that other antibiotics that already target InhA have already been found, and resistance to them doesn’t confer resistance to Pyridomycin.

I thought that was one of the neater points of this as well. The paper in the last link has a succinct bit in the discussion about how (as you know, Bob) isoniazid needs to be activated by another bit of the bacterium before it can bind to the site where it can then proceed to muck up fatty acid synthesis. All the bacterium needs to do to gain resistance is alter the activation bit. Or as they put it:
Although isoniazid is certainly the most effective known inhibitor of InhA in M. tuberculosis, it is a pro-drug requiring activation by the KatG catalase–peroxidase to form an adduct with NAD. Clinically significant resistance to isoniazid is mainly attributed to loss or alteration of KatG activity.
Pyridomycin, on the other hand, doesn't require this metabolic handholding.
posted by Panjandrum at 9:43 AM on September 21, 2012


The problem with TB is that it has very slow life processes. Normal bacteria in favorable conditions will divide about ever half hour. TB in favorable conditions divides about twice a day.

Most antibacterial drugs are at their most effective during cell division. For normal bacteria that means about ten days of treatment, sometimes less. For TB, you have to take the drugs reliably for at least six months.

Only some people don't. As mentioned above, prison inmates, for instance. Homeless people are another example of this: they feel awful, go somewhere and get free medical care including free drugs, and they take the drugs until they feel better -- but are not yet cured. Then they stop, and a few months later the disease is back, only now it's somewhat drug resistant.

The only way to make sure that doesn't happen is to confine such people until the full treatment is complete, but that has obvious human rights issues. (However, in the US it is legal to do this, and once upon a time, before the development of any drugs, TB patients would be confined for life to prevent them from spreading the disease.)

Or there's a different answer: don't treat people who aren't expected to complete the treatment. That way they die without their disease becoming drug resistant. That's cold and heartless and unethical -- but so is creating untreatable diseases.
posted by Chocolate Pickle at 10:37 AM on September 21, 2012 [2 favorites]


"Seems to me that the mycolic acid should be considered part of the cell wall since it is covalently linked thereto. Here's a figure from that review showing the structure."

From a nomenclatural perspective, 'cell wall' is a pretty profoundly terrible term that should have been long ago banned from use in the literature to refer to anything other than the rigid pectin layer of plant cells. Outside of plant cellular biology, though arguably also algal cell biology, 'cell wall' has been used to refer to just about every component and combination of components of the membranes of prokaryotic cells imaginable in the published literature. Thus, by meaning everything, it really means nothing - and that is a problem that creates confusion like this.

It wasn't always this way, and there really is a component of cell membranes that is pretty analogous to the cell wall of plant cells - peptidoglycan; it and the pseudopeptidoglycan layer of Archaea alone are really the only vaguely defensible definitions for 'cell wall' in prokaryotes. Kinda like in plant cells, it forms a hard rigid shell, provides structure, and allows for turgid pressure to build up. However, since its been used to mean so many other things in inconsistent ways we really should abandon it entirely. The figure in the review you just cited seems to include both the peptidoglycan layer, the mycolic acid layer, and the stuff in between of mycobacteria as part of its definition for ‘cell wall’ in mycobacteria, and I'm sure there are other examples of that definition in the literature, but it could hardly be said to be universal or terribly meaningful. It does make a sort of sense but it is uniting two fundamentally different kinds of materials - by way of analogy, something about the consistency of ear wax and something about the consistency of fingernail. Others would call the whole membrane structure the 'cell wall', more would call only the peptidoglycan the 'cell wall', a few would call everything but the lipid membrane the 'cell wall', and some now even call the mycolic acid layer an independent outer membrane.

The nomenclature, even when used well, for membranes of bacterial cells is pretty fucked up and confusing. For example, the best word we have for meaning the whole damn thing together is 'membrane', or not really that helpfully 'cellular membrane', which doesn't really differentiate between that and its other meaning of the lipid bilayer, or 'lipid membrane.' It all kind of sucks and we all try not to get mad at each other because whenever someone says something stupid, unless spectacular, the better alternatives aren't really that much less stupid.
posted by Blasdelb at 10:52 AM on September 21, 2012 [2 favorites]


Homeless people and prisoners and people who are being "frugal" and people who thing that drug companies are just running a big scam and.... The easiest way to not treat people who you don't expect to complete the treatment is to not develop drugs that aren't going to be administered by physicians. Most people are pretty terrible at drug compliance.
posted by Kid Charlemagne at 10:56 AM on September 21, 2012


Also, my name is totally Bob and I've had to do more than a few double takes reading this thread.
posted by Blasdelb at 10:57 AM on September 21, 2012


Blasdelb: "From a nomenclatural perspective, 'cell wall' is a pretty profoundly terrible term that should have been long ago banned from use in the literature to refer to anything other than the rigid pectin layer of plant cells. "

I'm glad to hear you say this. I'm a layman's layman at this stuff, but one thing I definitely remember from 9th grade biology is that the only cells with "walls" are plant cells. I've come across the term used with regards to animals' cells many times since then, and it's always befuddled me when I see it.

Also, TB sucks. Can we get a kickstarter campaign or something to "smallpox" it?
posted by InsertNiftyNameHere at 12:45 PM on September 21, 2012


Chocolate Pickle, treatment options don't have to be so bleak and Darwinian, there is DOTS, which requires neither criminalizing a disease nor denying sufferers treatment. The problem with treatment compliance in TB is much less a problem of the sufferers than dysfunctional public health systems as function of societies that intrinsically devalue the lives of those most likely to get infected (prisoners, the poor, etc.).

DOTS implementation may require widespread political will and both economic and social capital, but envisioning a society where the program is the standard is far easier than picturing the kind of pathological society where TB patients are turned away for not being trustworthy enough. The dichotomy of confined or refusal strikes me as a kind of "shoot the queers" solution.
posted by Panjandrum at 2:23 PM on September 21, 2012 [1 favorite]


Panjandrum, I'd like to know what they think "Short Course" means, in terms of time.
posted by Chocolate Pickle at 2:45 PM on September 21, 2012


chocolate pickle - maybe this? NEJM "short course tuberculosis treatment" - 3 months for latent tb infection. there's a CDC release about their recommendations.

the short course treatment is pretty exciting to me, as both the drugs used in it are used in pregnancy (my field), and most of the patients i work with only get contact, let alone regular contact, with healthcare during their pregnancy.
posted by circle_b at 3:26 PM on September 21, 2012


Well, three months is better than the six I thought it would take, but it isn't exactly "short" when compared to the treatment regimen for most normal bacterial diseases (7-10 days).

And there's still the question of how you make sure that the patient completes the treatment.
posted by Chocolate Pickle at 5:04 PM on September 21, 2012


As for how you make sure the patient completes the treatment, that's built into DOTS therapy. It is, after all, "Directly Observed Treatment." Ideally there are community health workers whose job is to observe and ensure that patients continue on regular treatment.

This therapy protocol was directly developed because of the long treatment plan of TB leading to non-compliance (and then onto MDR/XDR-TB) and has found to be a cost-effective and efficient way of combating TB. It's effective because the thrust of DOTS is just basic epidemiology: improve surveillance and follow-up. Basically, make health care professionals aware of the problem and then ensure they have the education and resources to make sure that an effective treatment plan is implemented.

Maybe that sounds like an unrealistic goal, but InsertNiftyNameHere brought up smallpox so I might as well do a cursory comparison. Smallpox was a disease that had a short course and an effective vaccine. TB, on the other hand, has a long course and a fairly inefficient vaccine. The public health measures that eliminated smallpox won't work with TB. I Think it was ID Rockstar Paul Farmer who once said that the problem with TB is that it never really went away, it just hid out in disadvantaged communities, which eventually led to the emergence of MDR-TB.

So we end up with a disease that has a pernicious latent period with the requirement of long and involved treatment course. The solution is obvious: to have wide surveillance paired with an actively involved healthcare system. The difficulty is not in the development of the treatment, but its implementation.
posted by Panjandrum at 6:53 PM on September 21, 2012


Blasdelb - damned fine, first rate science summary and very well put.

That's not the way to engage laypeople. <sigh> I've been guilty as hell (and not even nearly as good compared to what you've been doing in this thread) and I think that a don't even begin to know what would be a good start to a "best practices" for talking about highly specialized subjects to the lay audience.

Especially when said lay audience can have such highly disparate levels of education. Used to be that you could make assumptions of your audience based on whether they had a grade 12 education, or "college education," or a "degree."

Different times, now.

posted by porpoise at 8:15 PM on September 21, 2012


Panjandrum: "InsertNiftyNameHere brought up smallpox so I might as well do a cursory comparison. Smallpox was a disease that had a short course and an effective vaccine. TB, on the other hand, has a long course and a fairly inefficient vaccine. The public health measures that eliminated smallpox won't work with TB. I Think it was ID Rockstar Paul Farmer who once said that the problem with TB is that it never really went away, it just hid out in disadvantaged communities, which eventually led to the emergence of MDR-TB."

I think you make excellent points, at least to this layman, but I just wanted to interject and say that I didn't mean for my comment to derail the discussion among you folks who truly know about this stuff.

I only mentioned smallpox because it seems, to me, to be humanity's one truly astounding victory against diseases (polio just might be next, AFAIK). I have also, though, been made aware from info I've come across that smallpox could be considered one of the "easy" problems. e.g. human to human only (no other hosts involved), and, as you point out: short course and very effective vaccine.

Again, sorry for the potential derail, but I am a member of the ignorant masses who will need to know more about this and how best to deal with it if we ever have a chance of defeating it.

I sincerely hope I haven't sounded antagonistic or rude in any way whatsoever. That sort of attitude was the furthest from my intentions!

Anyway, let's now return back to the details of this FPP.

BTW, MeFi ROCKS!
posted by InsertNiftyNameHere at 9:22 PM on September 21, 2012 [1 favorite]


Smallpox was chosen by the WHO for that effort quite deliberately because it was one of the easy ones It was a disease exclusively of humans, which was passed only through personal contact, for which there was a vaccine which was cheap, effective, and very safe, which could travel well and could be administered by relatively untrained personnel using airgun injectors.

Even so, it wasn't practical to vaccinate the entire human race, and they didn't try. Instead they blanketed outbreaks and vaccinated everyone in that area, so that the disease would burn itself out for lack of new victims.

You're right that it's a miracle, but the lessons from that miracle don't map to diseases like Malaria or Tuberculosis. Those can't be controlled using the same approach. The devil is in the details.
posted by Chocolate Pickle at 11:56 PM on September 21, 2012


Chocolate Pickle: "Smallpox was chosen by the WHO for that effort quite deliberately because it was one of the easy ones It was a disease exclusively of humans, which was passed only through personal contact, for which there was a vaccine which was cheap, effective, and very safe, which could travel well and could be administered by relatively untrained personnel using airgun injectors.

Even so, it wasn't practical to vaccinate the entire human race, and they didn't try. Instead they blanketed outbreaks and vaccinated everyone in that area, so that the disease would burn itself out for lack of new victims.

You're right that it's a miracle, but the lessons from that miracle don't map to diseases like Malaria or Tuberculosis. Those can't be controlled using the same approach. The devil is in the details.
"

Did you read my most recent comment? (Who the F said anything about the entire human race being inoculated to win the fight against smallpox or any other disease?) I thank you for your expert opinion, but I can't find a single thing in your above statements that I disagreed with in my comments.

Anyway, this is pointless. I only remarked to the extent I did so this WOULD NOT become a derail, and you still had to interject when your points were either already acknowledged or made for you. Now, can we please get back to the topic? Some of us are more interested in facts and learning things rather than who can win the high school debate. Jeez!
posted by InsertNiftyNameHere at 12:35 AM on September 22, 2012


Good timing: TB cases increasingly resistant to all drugs, study warns
posted by homunculus at 3:27 PM on September 22, 2012 [1 favorite]


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