Tuesday, 20 September 2011

Every Bug for Themselves! How Changing Enzymes Create Resistant Infections

Sooner or later pretty much everyone is going to have to take a course of antibiotics. Whether it’s a bacterial chest infection, strep throat, or a cut finger that gets out of hand, a bottle of “twice a day, with food, until finished” meds will eventually find its way onto our kitchen counters. Like most of the medicines we take, many of us don’t worry about how they let us reclaim our own bodies, as long as our symptoms get better and stay that way. Unlike many of the medications we take,  antibiotics target processes that aren’t controlled by our own bodies, but rather by the chemistry of another life form. Unfortunately for us, these little buggers multiply faster than we do, adapt faster than we do, and have big population numbers on their side. Lets take a look at how antibiotics effect bacterial enzymes, and what the bugs do to bite back.

In humans, enzymes are vital catalysts for much of the chemistry we need to sustain life. This includes breaking down our food, building up new body parts, and keeping everything repaired, supplied with nutrients, and responsive to our environment. The same is true for bacteria. Fortunately for modern medicine, many of the mechanisms and enzymes bacteria use are very different from those in humans. Additionally, there are many things that bacterial cells do, such as building cell walls, that human cells don’t. Many antibiotics work by targeting the enzymes that are different between the bacteria and people. As an example, bacteria need their cell walls to live, so a drug that shuts down an enzyme needed to make the cell wall will kill the bacterium but will not affect human cells that don’t have the same cellular machinery. By picking on enzymes bacteria need that humans don't have, antibiotic drugs are able to kill bacteria, and fight bacterial infections, without causing damage to the human patient.

If antibiotics kill bacteria by shutting down enzymes needed for important chemistry, how can misuse of antibiotics result in resistant strains of bacteria? To understand the answer to this question, we have to understand that bacteria reproduce much, much faster than people do. In fact, some bacteria produce more than one new generation per hour. To reproduce they have to copy their DNA, and sometimes mistakes are made resulting in changes to the DNA sequence. These changes can result in changes in the sequences of proteins within the cell, some of which will be in the enzymes targeted by the drugs. Some of the changes might result in enzymes that don't work and a new bacterium that will die, but the odd bacterium will coincidentally have an enzyme that still works, but is no longer affected by the drug. This can happen if the place the drug binds to the enzyme is disrupted, the enzyme interacts differently with something else in the cell, or even if the enzyme itself is not changed but something else interacts with the drug, stopping it from effecting its original target. Changes can also occur in other enzymes so that they pick up the catalytic slack and the original enzyme isn’t necessary anymore. 

Individual DNA mutation events are pretty infrequent and random, so a very very small percentage of the bacterial population will experience a mutation leading to a change in the target of a specific drug. These lucky few, however, will survive when the drug kills all of the bacteria without a lucky mutation. So in a typical infection with many drug-susceptible bacteria and a tiny percentage of drug-resistant bugs, the drug will kill the bacteria that it can, and those resistant to the drug will survive, eventually making up the whole bacterial population in that patient. This means that using antibiotics selectively encourages the growth of resistant bacteria, and every time a single antibiotic is used, resistant strains have an opportunity to become more common.

Antibiotics can help us to get rid of infections by killing off most of the bacteria and giving our immune system a chance to fight off the resistant few. Also, these drugs are often used in combination for tricky infections so that bugs resistant to one drug will probably be killed off by the other. The fact remains, however, that all of the antibiotics currently available are getting less and less effective as more and more resistant strains emerge. In the face of this problem, we all need to be careful about the way that these drugs are used, effectively conserving the resource of antibiotic effectiveness. So the next time you have the option to buy a product with an antibiotic added, consider the old-fashioned version. 

Sometimes all you need is soap.

Wednesday, 7 September 2011

Moonlighting Enzymes: Supporting Keg Parties Everywhere

Our lab is situated in close proximity to a high concentration of fraternity houses, and as the fall term commences the warm autumn atmosphere reeks of fresh loose-leaf, cheap beer, and hang-over bacon. Any truly savvy and overindulgent undergrad should be writing a little thank-you note to one of the crucial factors that enables this year-opening bash: the enzyme alcohol dehydrogenase (ADH). This little microbrew miracle has been helping humans indulge in handcrafted libations for around nine thousand years and is perfectly suited to this function. Or is it? A recent study questions the evolutionary history of ADH and suggests that it might have more important things to do than aid in our enjoyment of an evening martini.

            Given that enzymes are integral components of so much of our body chemistry, it can be hard to remember that they haven’t always been there. Just like everything else, they had to come, to evolve, from somewhere. ADH is no exception. These days, it’s studied as the first enzyme in the metabolic pathway helping us to break down ingested alcohol (ethanol). Without it, we couldn’t efficiently clear alcohol from our systems and it could accumulate to lethal levels over the course of a lively cocktail party. In fact, one form of the enzyme acts in our stomachs, starting to break down the intoxicating molecule before it ever reaches our bloodstream. But where and how did ADH evolve? Were the molecules in our prehistoric ancestors preparing for a time when our species would start breaking out the booze?

            The rules of enzyme evolution parallel those of organism evolution: an ecological (or functional) niche has to exist before the process of natural selection can result in something filling that niche. In the case of ADH this means the availability of ingestible alcohol. If there is no dietary alcohol to break down, there should be no enzyme evolution specifically to break it down. By far, the greatest source of alcohol available for animal consumption is fermentation of fruit sugars, so the appearance of fruit in the prehistoric world should predate that of ADH. This is assuming that ADH really did evolve to break down alcohol. It is this assumption that is being questioned by a group of Mexican scientists.

            In a sobering study examining the functional capacities and evolutionary histories of a range of ADH enzymes, the real purpose of human ADH was called into question. In actuality, humans have several forms of ADH from three very different classes of enzyme using very different means to achieve ethanol transformation. Only one class of ADH is considered to be important for human alcohol breakdown. As it turns out, this class of ADH evolved before the appearance of fruit-bearing plants. That is to say that the type of enzyme we use today to reduce both inhibitions and alcohol toxicity showed up before there was any alcohol to indulge in.

If ADH’s only job was to enable aperitifs, it would not have evolved to do so before the functional niche existed. Instead, it is more likely that ADH has a somewhat serendipitous ability to metabolize the alcohol we drink, and we exploit that ability. In fact, all of the human ADHs are better at catalyzing transformation of different (non-liquor-related) compounds in our bodies, such as bile acids and serotonin. It seems that the party-pleasing activity human ADH is best known for is a handy trick this enzyme would file under “other abilities.”