Antibiotic Resistance in the news again

The BBC reported today a new study from the research team of Professor Jianzhong Shen at the Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, Chinese Agricultural University. The work describes a more threatening form of resistance to a "last resort" antibiotic and was published in the medical research journal The Lancet. The issue of antibiotic resistance is high on the agenda of health care leaders and politicians and therefore not surprisingly it is often in the news. This is a short post to help you [and your families] to understand what all of the "fuss is about". And of course, it is National antibiotic awareness week!

Antibiotics are drugs, the first of which was penicillin, discovered by Alexander Fleming (pictured on the right, first left) and developed by the Australian pharmacologist and pathologist Howard Florey (right), first at Sheffield and then at Oxford with Ernest Chain (middle): all three shared the Nobel Prize for Physiology or Medicine 1945. Antibiotics are used to treat humans (and don't forget animals!) who have been infected with a microbe. The microbes that can be killed by antibiotics are are usually bacteria (also called prokaryotes, since their genomes [their DNA], are not contained within a nucleus) such as Escherichia coli (E.coli) or Clostridium difficile (C.diff). They can also be more complicated eukaryotic microbes, such as  fungi like Aspergillus and Fusarium that cause skin infections: these are also treated with antibiotics (sometimes also called antifungals). The treatment of the more persistent infections like Tuberculosis (TB), usually requires two courses of 4 antibiotics: isoniazid and rifampicin every day for 6 months, and pyrazinamide and ethambutol every day for the first 2 months. As you can imagine, this is a challenging routine for anyone, but even more so in remote parts of the world.

Antibiotics are not one type of molecule. Penicillin is called a beta-lactam, by the chemists who make them. Drugs like penicillin act on the enzymes that are essential for building the bacterial cell wall. My "favourite" class of antibiotic is ciprofloxacin (marketed as "cipro", for obvious reasons!). This drug, stops bacteria from completing the separation into two new cells at the end of cell division. It actually blocks the bacterial enzyme, DNA Gyrase. Our understanding of DNA Gyrase has formed the basis of the life work of an old friend Professor Tony Maxwell, first at Leicester and now at the John Innes Centre in Norwich. And currently, Tony is pioneering the use of beetles for the discovery of new antibiotics.


The targets of antibiotics are usually proteins,  including enzymes like DNA gyrase, or membrane channels and pumps such as the Tetracycline transporter (the figure on the RHS shows the arrangement of a typical drug resistance "efflux pump" such as the one that pumps out the drug, tetracycline, thereby making the bacterium resistant). Sometimes the antibiotics act on RNA-containing molecules and in particular the ribosome, the cell's protein synthesis "factory". You can more read about the classes and targets of antibiotics in scientific detail here, or more medically here.

So what is antibiotic resistance, how does it arise and why should we be concerned about the latest story? Charles Darwin lends his name to the theory of evolution, in which populations of organisms adapt with time, to meet the challenges of their environment. All of which is of course propelled by a process we call Natural Selection. We now know in some cases, in molecular detail, that Darwin was right and that his ideas provide an explanation for the emergence of antibiotic resistance. In other words it doesn't come as a surprise to scientists, but it does illustrate the responsibility that scientists have in advising on the most appropriate use of antibiotics (in the same way they should advise politicians on decisions relating to energy sources, IVF,stem cell therapy for example).

All genes, including those that confer resistance to antibiotics, such as penicillin, can change with time, through natural  processes that copy our genomes. Remember we, and microbes, have an inbuilt capacity to shape our genomes, through relatively common single letter changes (for example, G becomes C or A becomes T), or less frequently by the movement, or loss of parts of genes, entire  genes and even groups of genes). These mechanisms are the engines of evolutionary change. But they also open the door for antibiotic resistance.

Consider a gene encoding a protein, such as an enzyme; and now let that enzyme be essential for bacterial growth. A molecule is isolated from another microbe: a Streptomyces species, perhaps, or a plant, that inhibits this enzyme. Think of it like throwing a stick into the spokes of a moving bicycle (I say think, but don't try it!). The stick, when thrown at a moving bike, will either miss the bike completely; it may bounce off the spinning wheel, or occasionally it will slot between two spokes. In the latter case, the bike will immediately stop and the cyclist will possibly fly off over the handlebars. (Yes this has happened to me!) The stick is the antibiotic and some of the antibiotic you take, just like any drug, doesn't hit the target (but that's for another post). If the bicycle manufacturer adds a wheel with no spokes (think of Sir Chris Hoy, riding round a velodrome), then the stick will no longer stop the bike. The bike is now "resistant". The cycle inventor wasn't trying to design a bike that would be resistant to a stick thrown by one of the spectators, s/he was trying to improve Team GB's chances of Gold. In the same way changes are introduced into bacterial genes and therefore their corresponding proteins, through the in-built mechanisms of evolution. If this makes those proteins resistant to the antibiotic that the doctor has prescribed, then, with time, this "mutant" strain will grow in number and will spread in the population: even around the world!

The introduction of antibiotics since 1940, is a form of "Natural Selection".  It is no different in principle than selecting the features of a dog for breeding. However, one of the  consequences of what we now believe is the excessive use of antibiotics, is the emergence of resistance. We humans, have effectively promoted the spread of antibiotic resistant microbes.

I started by alerting you to recent BBC article. So why is it important? There are some antibiotics that are called "last resort", where the development of resistant genes has either only been reported very recently, or has been effectively  "contained". In the case of Colistin, a class of antibiotic based on a parent molecule called polymyxin. This is a cyclic peptide molecule (see diagram, LHS) that is produced by the bacterium  Paenibacillus polymyxa var. colistinus. It solubilses the bacterial membrane just like a detergent. Because it is more like a general purpose detergent, it doesn't have the same level of specificity as our stick above. Think of it as a large boulder thrown at the bike! Knocking off the cyclist and crushing the bike. In other words as my old maths teacher used to say of my solutions to problems: "it is correct, but as usual Hornby, you have used a sledge-hammer to crack a nut!". But when the nut-cracker doesn't do the job, sometimes you do need a sledge hammer. (I would say in my defence!)

Such classes of compounds do also have severe side effects; in the case of colistin (sold as Colymonas or Koolistin), there are mainly kidney function issues. However, the decision to prescribe any drug in an emergency, will be a judgement made by the doctor based on whether the side effects represent an acceptable risk compared with the threat to a patient's life. 

Report of resistance to colistin are very rare and have always been associated with mutations in the bacterial genome, its chromosome. However, Professor Shen's group have shown that the resistance mechanism is a result of a plasmid-borne gene, which effectively masks the cell membrane from the hole punching effect of the antibiotic. Without explaining the details of plasmids, think of them as tiny versions of bacterial genomes. A bacterial genome will have around 3 000 genes arranged in a single large circle of double stranded DNA. Each circle is copied during cell growth and then the two daughter cells acquire a single copy (remember this is the process that is targeted by cipro, above). Plasmids, in contrast have only a dozen genes (so they are a few hundred times smaller, circles of DNA). They are also able to copy themselves (or replicate) so that a bacterium may posses between a few and a few hundred plasmids for every chromosome. Worse still, in some situations these plasmids can move around populations of bacteria and gatecrash. The Beijing findings, demonstrate that a plasmid can transmit resistance to colistin, a last resort antibiotic, at a level that is very difficult to "contain". This result is a timely reminder of the challenges facing the world.
 
Can antibiotics be used to treat viral infections? The term antibiotic refers to drugs that will stop the growth of a living microbe. A virus is not a true living organism. A virus must "steal" parts and functions of the cell it infects in order to copy itself and if pathogenic will cause us health problems. Think of the virus as a passenger on the bike (above). If the stick wrecks the bike, and even the rider, the passenger often walks away unharmed. If we want to prevent a viral infection taking hold, we generally administer a vaccine: which blocks the viruses ability to infect a cell. If the virus possesses enzymes or RNA molecules, that are not found in humans, for example the enzyme reverse transcriptase is the "hallmark" of retroviruses like HIV and Ebola, then drugs can be used to inhibit these virus-specific processes. We refer to such drugs as antivirals. They are not the same as antibiotics. If antibiotics are prescribed to treat a viral infection they will have no effect and may further promote the emergence of antibiotic resistant bacterial strains. This is why politicians are cautioning the medical profession against "over-prescription" of antibiotics.

I should say that a decision to prescribe or not prescribe is never easy. The doctor may be faced with a very sick patient, presenting with a high temperature. The speed with which a diagnosis can be made to  distinguish between a viral or bacterial infection may require a default decision to prescribe an antibiotic. This is of course completely understandable. But when antibiotics are routinely being added to animal food in an unregulated way, it is clear that people need educating and controlling. Professor Timothy West from Cardiff specialises in these area and you can read more about his work here and at the BBC.

Finally, I believe that all school classrooms should have posters on the wall made by students explaining the properties and the sensible use of antibiotics. This will hopefully help buy us some time to produce new antibiotics! Why not have a competition to design the most informative poster?