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Antibiotic Resistance AMA

I remember my first glimmer of understanding about the vast quantities of antibiotics fed to livestock in order to fatten them for market with less feed. This was one day in the 1980s, in the days before the WWW made it so easy for those of us who want to, to learn and share such information. I was part of a team that walked into the impressive lobby of Eli Lilly in Basingstoke on a mission to consult to their sales management and VP on HPs ground-breaking experiences with Sales Force Automation. A huge plaque celebrating the sales of antibiotics into agriculture, prominent high on the wall of the lobby, caught my eye, and got me thinking. Later, working with their team, I uncovered more about the story.

Now decades later, society at large may be about to pay the ultimate price for this practice which has contributed to antibiotic resistance.

Professor Sarah Fortune of Harvard's Department of Immunology and Infectious Diseases and Eric Rubin the Irene Heinz Given Professor of Immunology and Infectious Diseases, held a Reddit AMA (Ask Me Anything) on  how drug resistance evolves in bacteria.

The emergence of antibiotic resistance is a large, evolutionary scale problem. However, as individuals, we each have a role to play in limiting the further emergence of antibiotic resistances. First, a lot of antibiotic resistance appears to be driven by the agricultural use of antibiotics as growth enhancers. Thus, we can be savvy consumers and support and be willing to absorb the costs of the efforts to get antibiotics out of the meat industry. Second, we need to be advocates for active solutions to the lack of pharmaceutical interest in antibiotic development. And finally, yes, take antibiotics only when you need them (not for viral infections) and according to instructions.

More here:

Sarah Fortune:

Eric Runin:

Diagram depicting one recognized way in which bacteria may be resistant to antibiotics: if the antibiotic functions by blocking the active site of the enzyme, the bacteria may evolve to produce an enzyme that will not allow the antibiotic to bind to its active site. (This diagram is modeled specifically on the way some strains of Staphylococcus aureus have evolved to resist the beta-lactam antibiotic methicillin by expressing the mecA gene.) 1- Both enzymes are structurally similar, but differ in the kind of substances they will allow in their active sites. (The differences between the two may actually be much more subtle than what is implied by the image.) 2- Both enzymes carry out normal functions in the bacterial cell. (In this case, the enzymes are depicted making cross-links in the bacterial cell wall, a function which is crucial to bacterial cell survival and replication.) 3- The beta-lactam antibiotic fits in the active site of the antibiotic-sensitive enzyme, but not in that of the resistant enzyme. 4- Once in the active site, the beta-lactam ring of the antibiotic springs open, permanently inactivating the sensitive enzyme. The resistant enzyme, however, is totally unaffected; it is free to continue carrying out its normal function in the bacteria.

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The history of penicillin and its development.

Melvyn Bragg and guests discuss penicillin, discovered by Alexander Fleming in 1928. It is said he noticed some blue-green penicillium mould on an uncovered petri dish at his hospital laboratory, and that this mould had inhibited bacterial growth around it. After further work, Fleming filtered a broth of the mould and called that penicillin, hoping it would be useful as a disinfectant. Howard Florey and Ernst Chain later shared a Nobel Prize in Medicine with Fleming, for their role in developing a way of mass-producing the life-saving drug. Evolutionary theory predicted the risk of resistance from the start and, almost from the beginning of this 'golden age' of antibacterials, scientists have been looking for ways to extend the lifespan of antibiotics.

Listen here (stream, podcast, download MP3, plus lots of links):


Also, here's a discussion of antibiotic resistance.

This week we're dedicating the whole programme to one of the biggest threats to humanity. We're already at 700,000 preventable deaths per year as a result of antibiotic resistance, and the O'Neill Report suggests that this will rise to 10 million people per year by 2050. Today, we're focussing on the attempts to discover new antibiotics, and alternative therapies for combating bacterial infection. Firstly, we wanted to know why new antibiotics aren't being produced. Dr Jack Scannell, an expert on the drug development economics, told Adam Rutherford why money has been the main barrier.

Most of the antibiotics we use were discovered in the mid-20th century, but as the threat of drug resistant infections increases, the race is on to find new organisms that make novel medicines. We have only identified a tiny fraction of the microbes living on Earth and are "bioprospecting" for useful ones in wildly different locations. Microbiologist Matt Hutchings has been looking to the oldest farmers in the world - leaf cutter ants.

From exotic locations to under your fridge: Dr Adam Roberts runs a scheme called Swab and Send. It's a citizen science project that asks members of the public to swab a surface and send the sample to him – he'll analyse them to look for the presence of new antibiotic-producing bacteria. We joined in the hunt by swabbing spots around the BBC: Adam's microphone, the Today programme presenters' mics, our tea kitchen's sponge, the revolving entryway doormat, and lastly, the Dalek standing on guard outside the BBC Radio Theatre.

Antibiotics are not the only weapon in the war against bacteria. A hundred years ago, a class of virus that infect and destroy bacteria were discovered. They're called bacteriophages. Phage therapies were used throughout the era of Soviet Russia, and still are in some countries, including Georgia. Phage researcher Prof Martha Clokie told us whether phage therapy might be coming to the UK.

Listen here (stream, podcast, download MP3, plus links):


An unsung hero of getting ready for saving lives during and after D-Day was Norman Heatley. He developed the extraction technique for manufacturing bulk penicillin.

Norman Heatley's innovations meant that the team could extract and purify the penicillin. "He was the key technical man. He was also the man who quantified the activity and he introduced a clever assay for measuring the strength of penicillin. For a long time the measurements were known as Oxford Units of penicillin.

The next step was to test the drug on humans, but a much greater quantity of penicillin was required. Heatley discovered that the hospital bedpans he had acquired from the Radcliffe were a good place to grow the mould. He then commissioned a pottery company to make 1,000 square bedpans so he could manufacture the amount needed.

Six 'Penicillin Girls' were employed to help grow it and by early 1941 they felt there was enough to start treating humans. The first patient was Albert Alexander, an Abingdon policeman at the Radcliffe Infirmary. Though his condition improved they did not have enough penicillin and he eventually died.

The team then changed tact and began administering the drug to children as this required smaller amounts. They treated a child who was cured from his infection but died of complications. Then a series of patients were treated and they all recovered. In August 1941 this work was written up and that's when it really hit the headlines.

More here (Oxford local news):


What if Fleming had not discovered penicillin?

Alexander Fleming is often criticised for not being more pro-active in developing penicillin as a curative agent. Interestingly, it has recently come to light that a research grant was made to the UK Medical Research Council, as early as 1930 for Stuart Craddock, one of Fleming’s assistants who, during this period, worked on penicillin. The request was refused, and the page detailing the proposed grant has mysteriously been excised from, the otherwise complete, MRC records. Maybe someone was keen to avoid the ridicule for having refused to support the work that would possibly have made penicillin available a decade sooner. Perhaps the perpetrator of this academic crime should have relaxed, since it is unlikely that penicillin could have been produced, on an industrial scale, during the early 1930s and had it been so, then the axis powers could have shared its benefits during the Second World War.

More here (article):


Related posts:

Dorothy Crowfoot crystallographer:

Dorothy Hodgkin (in her own words):

Image: from Inside Science above.
Swab and Send:

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Penetrating Research
via +Susana M. 

Looking just like some probe developed by NASA, or ESA, to land on, grab and drill into a comet, but on a much smaller scale, sophisticated bacteriophages (viruses that infect and replicate inside bacteria), and even certain bacteria, deploy an amazing multiprotein macromolecular device that lands on, grabs, and penetrates target cell membranes. Now, the laboratory of Petr Leiman at EPFL has deduced, at an atomic level, how the twisting of the backplate (like some ballpoint pen or telephoto lens) is key to this complex penetrating mechanism.

To infect bacteria, most bacteriophages employ a ‘tail’ that stabs and pierces the bacterium's membrane to allow the virus's genetic material to pass through. The most sophisticated tails consist of a contractile sheath surrounding a tube akin to a stretched coil spring at the nanoscale. When the virus attaches to the bacterial surface, the sheath contracts and drives the tube through it. All this is controlled by a million-atom baseplate structure at the end of the tail. EPFL scientists have now shown, in atomic detail, how the baseplate coordinates the virus’s attachment to a bacterium with the contraction of the tail’s sheath. The breakthrough has made the cover of Nature, and has important implications for science and medicine.

More here (press release):

Type VI Secretion System (Wikip):

Bacteriocin (inc. R-type pyocins) (Wikip):

Full video (Flash 0:0:52):
Continues from GIF with a side view

Several systems, including contractile tail bacteriophages, the type VI secretion system and R-type pyocins, use a multiprotein tubular apparatus to attach to and penetrate host cell membranes. This macromolecular machine resembles a stretched, coiled spring (or sheath) wound around a rigid tube with a spike-shaped protein at its tip. A baseplate structure, which is arguably the most complex part of this assembly, relays the contraction signal to the sheath. Here we present the atomic structure of the approximately 6-megadalton bacteriophage T4 baseplate in its pre- and post-host attachment states and explain the events that lead to sheath contraction in atomic detail. We establish the identity and function of a minimal set of components that is conserved in all contractile injection systems and show that the triggering mechanism is universally conserved.

Paper (closed):
Abstract, figures, videos available

Related posts:

Image GIF extracted from video above.
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Dirty Babies

Research from Novartis, the Universities of Aalto and Helsinki in Finland, and the Broad (pronounced Brode) Institute has provided a possible partial explanation for the Hygiene Hypothesis.

It might be a good idea to let your babies get dirty outdoors.

It can be seen that as a country becomes richer and its people move away from subsistence farming and so remove themselves from close contact with animals, plants, and the soil that supports them, the population becomes more susceptible to autoimmune diseases like Type 1 Diabetes, certain kinds of Dermatitis, Psoriasis, etc. and to overzealous immune responses to common allergens – in the form of allergies.  

There is an appreciable difference between the gut microbiomes of babies in countries where climate and genetics are otherwise similar but where one is rich (at least in monetary terms) and the other country more agrarian.  These differences may have important implications for training the babies' immune systems and priming them appropriately for likely bacteria and allergens in the rest of their lives!

The border of Finland and Russian Karelia separates two starkly contrasting economies, with a sevenfold difference in gross national product existing between “westernized” Finland and the more traditional, agrarian Russian Karelia. Nearby, just across the Gulf of Finland, sits Estonia, a country that has seen rapid economic growth and increased standard of living since the dissolution of the Soviet Union over twenty years ago.

Consistent with the hygiene hypothesis, the prevalence of T1D is six times lower in Russian Karelia than in Finland, even though there is little difference between the two populations in the frequency of the genetic risk factors that predispose individuals to, or protect them from, the disease. Estonia, meanwhile, has seen incidences of autoimmune disease increase in a linear fashion as its economy has improved over the past two decades.

The DIABIMMUNE Study Group saw in these three countries the perfect “living laboratory,” where genetics, climate, and the make-up of the community were relatively consistent, but the economic structure and standard of living were key variables. Over several years, the group recruited and began collecting monthly stool samples from infants in each of the three countries. Along with the samples, from which they would identify and quantify the bacteria that made up the infants’ gut microbiomes, they also collected lab tests and questionnaires about such topics as breastfeeding, diet, allergies, infections, and family history. They evaluated all of this data, which was collected from over 200 infants from one month after birth to age three, to see whether connections might exist between disease incidence and what they found in the microbiome.

By characterizing the microbial content of the stool samples, the team found a sharp distinction between the microbiomes of Finnish and Estonian infants and their Russian Karelian counterparts: the gut microbiomes of the Finnish and Estonian infants were dominated by Bacteroides species, while Russian Karelian infants had an overrepresentation of Bifidobacterium early in life and an overall greater variability in their microbiomes over the course of the three years that samples were collected.

“We can only speculate why this difference in bacterial populations exists; what we could show was what implications that difference in populations might have,” says Tommi Vatanen, a graduate student at the Broad and University of Aalto and co-first author of the Cell study. To do that, the Broad research team worked with researchers from Novartis, including co-first author Eva d’Hennezel and co-senior author Thomas Cullen, to compare and contrast the genes of the bacterial species they’d found.

“That led us to the lipopolysaccharides,” Vatanen says.

More here:

Image by Steven Lee from article.

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Antibiotic Abuse

Jeremy Collier wants to use financial investment arguments to reform factory farming and to reduce the use of the human antibiotics that are still sold in vast quantities just to increase the growth rate of farm animals and to prevent the infections that would otherwise occur in intensive farming. Today, the Collier Foundation has released a letter from a number of fellow financiers asking the fast food, restaurant and pub industries they invest in to take action.

“Whilst we agree that antibiotics should be used for the treatment of sick animals, they should not be used to support irresponsible practices such as growth promotion or routine disease prevention of animals kept in closely confined and unsanitary conditions,” it says.

More at picture link.

FAIRR press release:

Jeremy Collier (Wikip):

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Seasonal Beings

The very composition of our bodies, it seems, changes seasonally and this has a bearing on the diseases we may succumb to.

A number of illnesses as diverse as cardiovascular disease, autoimmune diseases and psychiatric disorders have been known to follow seasonal patterns, but it has not been previously understood that human tissue function itself varies with the seasons.

Our susceptibility to disease is affected by some of the 4,000 protein-coding mRNAs, such as those for the autoimmune diseases, Type 1 Diabetes and MS, that have been found, by an international team of researchers, to have seasonal expression profiles.

On the other hand, it emerges that our immune systems are seasonal and seasons are location specific.  Depending on where we come from our immune systems over generations have evolved to be ready for times of peak necessity to defend against disease. In the Rainy Season, from late June to October, the immune systems of Gambians are primed for assault by diseases such as pneumonia, whereas in the North and the South of the globe, at two different times of the year depending on the hemisphere, our immune systems are at their peak in the Winter.

Professor Mike Turner, Head of Infection and Immunobiology at the Wellcome Trust said: “This is an excellent study which provides real evidence supporting the popular belief that we tend to be healthier in the summer. Seasonal variation to this extent is a fascinating find – the activity of many of our genes, as well as the composition of our blood and fat tissue, varies depending on the seasons. Although we are still unclear of the mechanism that governs this variation, one possible outcome is that treatment for certain diseases could be more effective if tailored to the seasons.”

More here:

Paper (open):

Image by Luke Price from article.

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Phage Phase Bacteria Wars

Without being unduly cynical about it phages were probably not developed by the big pharma companies for financial reasons while they had the cash cow of a basic stable of previously developed antibiotics and their variants. Now that these antibiotics are being out-competed by the rapid evolution of bacteria and the comparatively slow development of new classes of antibiotics, the drug companies are investigating how to patent something that is specific to each bacteria, has co-evolved with it, and is freely available in nature; bacteriaphages.

The need for new treatments for bacterial infections is desperate. From tuberculosis to E. coli, Klebsiella to gonorrhea, resistance to antibiotics is rising fast. Health officials around the world have warned that we may be entering a post-antibiotic era. It could mean deadly diseases become untreatable while surgery and cancer therapies would carry enormous risks of patients catching untreatable infections. Phages are one of the options that are often suggested as a possible new weapon against bacterial infection. It is an appealing idea - the enemy of my enemy is my friend. However as far as mainstream medicine is concerned it is just an idea. The field has not had the same level of funding as drug development. It means the big questions of effectiveness and safety still remain largely unanswered.

More here:

Also -
Smart Virus (by +Carl Zimmer via +Tommy Leung):


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Antibiotic-resistant Escapees

It has been found that simple chlorination in wastewater treatment plants may not be enough to kill certain bacteria that make an enzyme that can defeat the mainstay antibiotic used for treating antibiotic-resistant infections.  Furthermore having proliferated and escaped treatment these bacteria can share those genes that program for this enzyme.

“We often think about sewage treatment plants as a way to protect us, to get rid of all of these disease-causing constituents in wastewater. But it turns out these microbes are growing. They’re eating sewage, so they proliferate. In one wastewater treatment plant, we had four to five of these superbugs coming out for every one that came in.”

Antibiotic-resistant bacteria have been raising alarms for years, particularly in hospital environments where public health officials fear they can be transferred from patient to patient and are very difficult to treat. Bacteria harboring the encoding gene that makes them resistant have been found on every continent except for Antarctica, the researchers wrote.

More here:

Paper (open):

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Bacteria Wars

Here's a fantastic quality comment and paper from a bacteriophage expert in a Reddit thread that explores the possible weaknesses and disadvantages of phages.  We've heard quite a bit recently about the possible advantages of phages. As has been said before phages provide a comparatively untapped area of research for treatments to combat bacterial infections as our global abuse of antibiotics in the face of constant and rapid bacterial evolution leads to their likely catastrophic failure.

If anything the extraordinary specificity of bacteriophages is their greatest weakness as a treatment strategy as you need a bacteriophage against the specific strain ailing you for it to work, but there are currently three treatment strategies for using phages to combat disease in spite of their disastrous yet exciting specificity.

The first is to pre-generate cocktails of vast numbers of phages as they do in the Republic of Georgia at the Eliava Institute and BioChimPharm. At Eliava, they have three cocktails of phages that they update every 6 months against strains that they collect from around the country and don't really have a way to keep track of the functionally infinite number of phage strains that have been evolving in the cocktail since the 1930s. The first is intestiphage, which targets 20 different types of gastrointestinal diseases. One well-controlled trial of the concept was conducted in Tbilisi on 30,769 children back in the sixties, neighborhoods were split up with one side of each street treated prophylactically with a phage cocktail and the other a placebo. The result was a 3.8-fold decrease in dysentery incidence. A second cocktail, pyophage, is made against Staphylococcus, Streptococcus, Pseudomonas, Proteus, E. coli, and Enterococcus, the 6 major causes of purulent infections, it is used prophylactically on surfaces and wounds on a routine bases during surgery and for severe burns as well as against actively purulent wounds (like MRSA) with a high success rate. During the the most recent couple of wars there, soldiers carried spray bottles of phage for gunshot wounds and maintained shockingly low infection rates. The third is a relatively new one against prostititis.

While this pretty clearly effective against a whole bunch of infections, and is pretty clearly at least mostly safe, but there are good reasons why this strategy will probably never be used in the West. The only reports of adverse effects I've ever seen come from an abstract, for a long lost paper presented at a conference during the time that phage technology was considered a military secret, that described injecting volunteered conscripts with 106 times the therapeutic dose, which is generally applied topically, and they only got fevers; but there are very important theoretical harms. Many strains of pathogenic S. aureus as well as E. coli O157:H7 of Jack in the Box fame, Shigella, cholera, botulism, diphtheria, scarlet fever, and a whole bunch of described shrimp and insect diseases are in a sense not really caused by those bacteria but by the phages that infect them.

Essentially, all "live" phages can go through what is called a lytic life cycle when they infect a cell, shut down host metabolism and substitute it for their own, replicate their DNA, construct and pack viral particles, and then explode the cell for the new particles to hunt for more cells. This is obviously extremely lethal, which is great for us, but some phages (known as temperate phages and somewhat analogous to retroviruses) can also go through a lysogenic life cycle where instead of shutting down the hosts' metabolism, they turn off their genomes and wait. This creates what are call lysogens, sort of a phage/bacteria hybrid, where the phage hides and lets the host replicate it with its own chromosome when it divides. Now these temperate phages have an interest in their hosts doing well and sometimes have exotic genes, which get expressed independently of the host lethal ones, that often contribute to host success in weird situations, like pathogenesis.

Thus, for example, cholera isn't really caused by Vibrio cholerae like many of us may have heard but instead by the CTX-φ and TLC-φ phages. Vibrio are, for the most part, planktonic marine bacteria content to scavenge for low levels of exotic organic substrates in the oceans and leave us well enough alone. However, when infected by the temperate CTX-φ and TLC-φ phages, Vibrio cholerae suddenly gets a pathogenicity cassette of DNA with a type IV pillus (basically the business end of a phage on a string) and the profoundly nasty cholera toxin. Vibrio cholerae is like the pleasant dude who rolls around on the back of a truck in a jumpsuit picking up the garbage in front of your home, CTX-φ is the agent that turns him into a poison-syringe/grappling-hook wielding madman looking to feed off of your guts. These kinds of phage that are capable of going through this secondary type of lifecycle are pretty trivial to detect and avoid with pure phage stocks using modern sequencing but, while it is clear that the classical microbiology the Eliava uses strongly selects against them, there is absolutely no way to guarantee that they are not present in their ancient preparations even if they've never been reported.

There is also what they do in Wroclaw, Poland at the Hirszfeld Institute of Immunology and Experimental Therapy though. There they treat intractable infections resistant to all other treatment methods with phage preparations that are specifically designed for the strain causing the infection by isolating phage specific to the infection in question. They have success rates that range between 50% and 100% of cases, depending on the type of infection, and publish their findings in English. They suspect that the relatively low success rates with some kinds of infections has to do with the fact that most infections, by the time they see them, have had months, and more often years, to develop solid biofilms and avascular hiding places.

The solution favored by Western companies, the current front runners being AmpliPhi Biosciences taking the capitalistic approach and Nestle taking the socially responsible approach, is to isolate and characterize >5 phages with unusually broad host ranges. Indeed, a cocktail like this is now being used in just about all pre-cooked "ready to eat meats" (think baloney) on grocery store shelves now to prevent Lysteria and prolong shelf life. If you'd like a more in depth, but still accessible, run down of where we are as a community, where we've come from, and where we're going; the best review at the moment is still one that I should disclose that I am an author on. ♦︎

Edit: I took the liberty of adding a few paragraph breaks to aid readability.

More here:

♦︎ Much more here (pdf):

Earlier phage post:

+Rajini Rao's recent phage post:


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Antibiotic Resistance

If you are interested in the challenges of Antibiotic Resistance, Professor of Mathematical Biosciences at Exeter University, Robert Beardmore will be doing a Science AMA (Ask Me Anything) today on Reddit at 1 PM EDT ( 10 AM PDT, 6 pm UTC,

It is trivial to set-up a login to Reddit if you don't have one and the Science AMA is a properly moderated session where you can talk directly to Scientists and Mathematicians.

AMA here:

The original purpose of the fellowship was to create an evolutionary biology laboratory where we could use experimental systems, computational whole-genome sequencing approaches and single-cell assays to test mathematical predictions about rapid evolution, particularly as that term relates to antibiotic resistance in bacteria and fungi. The main idea was to understand whether any ideas from control theory could be applied to what is essentially a 'human behavioural problem', namely how, exactly, should we use antibiotics to treat disease and yet also mitigate resistance? Even professional scientists are not, perhaps, aware of just how fast Darwinian evolution can occur in microbial species but it is exactly this rapidity that allows mathematics to play a role in understanding the datasets we generate to probe this question.

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