New Antibiotics

This article from ScienceDaily.com talks about a new antibiotic that binds to bacterial DNA and kills bacteria within 2 minutes.

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The compound [Fe2L3]4+ is an iron triple helicate with three organic strands wrapped around two iron centres to give a helix which looks cylindrical in shape and neatly fits within the major groove of a DNA helix. It is about the same size as the parts of a protein that recognise and bind with particular sequences of DNA. The high positive charge of the compound enhances its ability to bind to DNA which is negatively charged. When the iron-helicate binds to the major groove of DNA it coils the DNA so that it is no longer available to bind to anything else and is not able to drive biological or chemical processes.

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New research at the University of Warwick, led by Dr Adair Richards and Dr Albert Bolhuis, has now found that the [Fe2L3]4+ does indeed have a powerful effect on bacteria. When introduced to two test bacteria Bacillus subtilis and E. coli they found that it quickly bound to the bacteria's DNA and killed virtually every cell within two minutes of being introduced - though the concentration required for this is high.

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While I'm sure this could have some amazing short term effects, how is this really any better than the antibiotic drugs we currently use? I concede that it will probably be harder for bacteria to develop resistance to the [Fe2L3]4+ because it does not target any specific sequence, it's not inconceivable that bacteria would. I mean, one way bacteria develop resistance currently is to simply pump the drug out of the cell before it does too much harm. Bacteria already have all sorts of ion pumps, I can't imagine there wouldn't be a way to pump out this one. I think it's also worth pointing out that being so effective at killing bacteria may actually be HARMFUL because it applies a very very high selection coefficient to the bacterial population which will result in much faster evolution.I don't think we will ever find the magical antibiotic bullet, but the game we're playing now, constantly fighting to stay one step ahead without really considering the evolutionary consequences can't last for long.I guess my topic for debate is: assuming "they" are able to develop this into an effective therapy, do you think it will succumb to the same fate that most antibiotics have? And, more generally, do you think the pharmaceutical companies will ever get it in their heads that the game they're playing is futile?Edited by Stagamancer, : No reason given.

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We have many intuitions in our life and the point is that many of these intuitions are wrong. The question is, are we going to test those intuitions?
-Dan Ariely

Thread moved here from the Proposed New Topics forum.

Healthcare has always been ultimately futile because we will eventually die not matter what. This is no reason to ignore the field completely. A new and effective antibiotic would save millions, perhaps billions of lives; not forever, but saved nonetheless. I don't see that as "futile".

Agreed, and I don't think we should, I just think the method is wrong. No, but instead of focusing on developing antibiotics that we know will be useless in 5 to 10 years, why not put more money into antibiotics with low selection factors, i.e. ones that prevent the host from dying without killing 99% of the pathogen. I know there's been some research into this (I can find the link to the one I'm thinking of just now) but I don't think it's enough.

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We have many intuitions in our life and the point is that many of these intuitions are wrong. The question is, are we going to test those intuitions?
-Dan Ariely

What fate have most antibiotics succumbed to?From my POV they kick ass. I had an infection. I took an antibiotic. The infection went away. Not so long as they're making money.

Well yes, obviously antibiotics have done some great things, and they still work for many basic infections. However, MRSA, multi-resistant TB, and other diseases have arisen, and continue to arise. Basically the original antibiotics we used to treat these have become useless.

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We have many intuitions in our life and the point is that many of these intuitions are wrong. The question is, are we going to test those intuitions?
-Dan Ariely

I admit, I only read the quoted parts of the paper(s?) but from what it sounds like, this could have an adverse effect on the person taking this drug as well as the virus. It seems like the [Fe2L3]4+ just bonds to DNA, not allowing it to do anything from that point. How can it differentiate between viral DNA and normal human DNA? If someone takes this, will it kill their own cells as easily as virus cells?

That's a very good point, and I thought of that too. It was originally developed as an anti-tumor therapy, so obviously, it can get into eukaryotic cells. I would imagine they'd have to develop some sort of delivery system that would only introduce it to bacterial cells (and keep it there), or find some way to make it specific to bacteria DNA, maybe based on either specific sequences or based on protein interactions. I don't really know how they would go about doing that, but it's another interesting idea to discuss.

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We have many intuitions in our life and the point is that many of these intuitions are wrong. The question is, are we going to test those intuitions?
-Dan Ariely

Just because bacteria have become resistant to their first line antibiotic does not mean we don't still have a choice of antibiotics with which to treat. In my lab the bacteria we culture from patient specimens are subjected to a whole battery of antibiotics to identify exactly what they are sensitive to. For example, MRSA could be treated with vancomycin, tetracycline, linezolid etc. The downside is that some of these alternative antibiotics may be less effective, and the doctors are more dependant on lab results to know how best to treat.As for the the article, very interesting. It's good that we are identifying more novel antibiotics, most of our current ones are just variants of a few different types (for example all the beta-lactam's are just variants on penicillin) which has contributed to antibiotic resistance. The other lesson to learn from past experience, is that if this does prove effective, we don't abuse tis compound, again allowing resistance to evolve.

I don't think we need to give up on our approach just yet, because it isn't as bad as you might think. Medical progress has, I believe, the capacity to out pace evolution. Allow me some ridiculous analogies to back this up:Suppose we are frontiersmen plagued by wolves which are eating our livestock. They can hide quite well and require some pretty tough work to hunt, and it isn't really practical to "clear" an area of wolves since they will either remain undetected or simply return after a hunt. We make a windfall discovery though; by putting on polarized sunglasses 90% of wolves will appear to have hot pink fur.Needless to say this technology makes it easy to spot and kill those wolves, but what of the remaining 10% that can still hide? Eventually all wolves will end up being the non-pink kind but will this prevent their eventual extinction? What if we come up with a second windfall that kills 90% of those remaining wolves, and we get this windfall within 2 months of the first?Back to reality: Wiping out large swaths of the bacterial population has benefits beyond the individual cases, even if we assume that the overall population size remains constant. The remaining scraps of resistant bacteria are lacking in the genetic diversity of the original population, and genetic diversity takes time to develop. The next method of bacterial death we develop will likely apply to a larger swath of the remaining population; ultimately the goal being to find an antibiotic effective against all of the remaining handful of strains.20% of bacteria might be resistant to Med A.
20% of bacteria might be resistant to Med B.
How many are resistant to both Med A and Med B? Much fewer.. maybe 5% overall.
How about Med C, specifically targeting that remaining 5%? Due to the specialization of the few strains, it gets all but 10% (.5% overall).
How about Med D, nearly useless on the original population since it only takes out 1% overall? On the other hand it completely obliterates every last strain that was resistant to A, B, and C.Evolution is powerful yet slow. Humans are the poster child of overcoming the evolutionary race: Wolves ate humans (among other things). Humans ran away, and got pretty good at it. Wolves got better at running. Humans got good at hiding. Wolves got good at finding. Humans banded together for protection. And humans made tools, such as spears. And guns, and trucks, and houses, and fences, and helicopters, and poisons, and traps, and... well, if not for our efforts to avoid it there wouldn't be any wolves left at all. There *are* still wolves out there now, but they are hardly a problem.

But here's the problem. When I mentioned antibiotics that kill 99% of the pathogen, that's only in the person who's been given the antibiotic, you're never going to kill 99% of the world population of a pathogen with antibiotics alone. Also, bacteria reproduce way faster (and evolve much faster) than wolves. Bacteria can develop resistance to drugs in a matter of days, and medical research just can't progress that fast. But those 5% are given a wide open playing field by the destruction of the rest of the population by those meds. Like I said, bacteria reproduce and spread pretty damn fast. Look at malaria, which is caused by a protist (multicellular) pathogen. Even so, there are multiple strains with various resistances to the drugs used to combat them. So far, we've never found a drug that can kill absolutely everything.Look, I'm not saying that pharmaceutical research is completely in the shitter. I know antibiotics have done and currently do all sorts of good; I'm glad I had them when I got strep throat. I know not all of them are useless. But the idea that "evolution is slow" does not hold for bacteria and many other pathogens. Basically what I want to see is an application of evolutionary theory to medical and pharmaceutical research, but it is not happnening.

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We have many intuitions in our life and the point is that many of these intuitions are wrong. The question is, are we going to test those intuitions?
-Dan Ariely

Yes, each patient is a microcosm of their own. We still go into the fight with all guns blazing though, we don't have to start medical science over every time. Oftentimes the patient's infections can be completely wiped out by our medicine and they never develop a resistant strain at all. You might do the same to the next, and the next. When I suggest that 99% of the world's population of the pathogen could be killed by antibiotics I obviously don't mean *instantly*, you obviously have to do it per-patient. Absolutely, I don't claim that wolves are perfectly analogous to bacteria. I don't think it is proper to say that bacteria necessarily develop resistances to drugs out of whole cloth, rather that selective pressures tend to make those most resistant to our drugs the most "fit" for the environment. Medicine is getting faster, but it does not *need* to get that fast if we can back infections into a corner through limiting their genetic diversity. Who knows, one day we might even have all the bases covered and be able to treat every possible avenue of infection, but until then what we are doing helps. Surely you are not suggesting that we should eliminate that open field by allowing it to be packed with competition?! "Good lord, this man is being ravaged by malaria! Don't worry though, we can limit its damage by simultaneously infecting him with some bubonic plague and various types of flu!" If we can treat 95% of the ailment we SHOULD! We are guaranteed for that treatment to be better than doing nothing, and the worst case scenario of an infection immune to everything we have would still be functionally equivalent to your original proposal. Sure we have, fire works pretty well. Of course we don't want to kill *everything*, we just want to kill very specific things. When we kill those things we often come up with new things we want to kill too, that require new methods. This does not mean that we shouldn't have killed those first things though.Applying evolutionary theory to medical and pharmaceutical research is well and good, but avoiding the use of antibiotic research is not the answer. By doing so we would give up our most powerful evolutionary advantage, our intellect. Basically it would be declaring bacteria the winners for all time, rather than the usual state of things where we are the winners except for a few isolated cases.It may be a legitimate concern that by continuing this arms race at the limit of both our capacities we are unlikely to win absolutely, and instead we would eventually be faced with a similar status quo as now, perhaps a little better, but that without medicine an infection would utterly destroy our immune system. I would counter this by saying that we are there already in other aspects of our lives; we need the advances of clothing and tools to be able to properly compete with the wildlife around us, so adding medicine to those "crutches" like fire and thumbs isn't the end of the world.

This is obviously ridiculous. My ACTUAL argument is that we should focus on reducing virulence, not killing everything we can. Who cares if you've got bacteria living in your that only give you the sniffles, or better yet, do nothing at all. Let's use that intellect we have to direct evolution in a beneficial way. That's a win for everybody. For example, Dr. Read, a researcher at Penn St., is looking into using a fungus as a pesticide for mosquitoes in malarial areas. The fungus tends to infect and kill mostly older mosquitoes, which, as it happens, also tend to be the ones that act as vectors for malaria. So, by attacking the older mosquitoes (that have already reproduced) you're not putting heavy evolutionary pressure on the mosquitoes to evolve resistance to the pesticide, but you're still cutting the incidence of malarial infection way down. That's using evolutionary theory applied to public health and medicine. This is more of what I want to see.Dr. Read also is doing research into how drug resistant and vaccine-escape (epitope) mutants erode the effectiveness of chemotherapy and vaccination. His research mostly deals with vaccines, but many of the arguments can also apply to antibiotics.

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We have many intuitions in our life and the point is that many of these intuitions are wrong. The question is, are we going to test those intuitions?
-Dan Ariely

This seems like it would actually place evolutionary pressure on increasing virulence since the window of infection becomes smaller. All he has managed to do is reduce the number of vectors without needing to produce a new pesticide. A better Band-Aid.Instead if we wanted to actually reduce their virulence we should place an evolutionary advantage on infecting something other than humans. We could do this by, say, destroying every human malaria case that we can find thus making human-infecting malaria strains less fit as they are less likely to reproduce. Logically then evolution would point them away from infecting humans.

Except, it could only increase virulence at the vector stage, and in order to get transmitted, a disease needs to not kill off its vector. I would actually predict there wouldn't be an increase in virulence then, because it would only serve to kill off it's own vector. It could even, perhaps force a host or vector switch that would make it all the easier to manage. Um, reducing vectors is a good thing. Vector-transmitted diseases tend to be more virulent than non-vector-transmitted ones. Eradication of the disease is pretty much not going to happen, so let's focus on decreasing virulence and transmission. By saying "destroying every human malaria case" do you mean killing people with malaria? If so, I assume you're trying to be satirical, and I don't really get why you're so against evolution based approaches to fighting disease. If that's not what you mean, then what exactly are you getting at?

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We have many intuitions in our life and the point is that many of these intuitions are wrong. The question is, are we going to test those intuitions?
-Dan Ariely