Antibiotics remain elusive

Science moves fast. Nowadays we don't have to wait hundreds of years to correct erroneous understanding as was the case with the gospel of ancient masterminds like Claudius Galen. Currently scientists can report something novel and discordant when compared with prevailing views and within less than ten years themselves become a target for scrutiny from their keen, attentive colleagues.

Recently it was reported that previous findings which indicate an existence of a general mechanism by which antibiotics kill bacteria could be wrong.

In 2007 researchers discovered that there might be "A Common Mechanism of Cellular Death Induced by Bactericidal Antibiotics". Scientists thought they found a discrepancy in classifying antibiotics into categories by their mechanism of action and that rather they shared one common way of killing bacteria.

All antibiotics elicited an increase in "production of highly deleterious hydroxyl radicals in Gram-negative and Gram-positive bacteria which ultimately contribute to cell death" and that "bacteriostatic drugs do not produce hydroxyl radicals". Thus, researchers concluded, "all three major classes of bactericidal drugs can be potentiated by targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response".

Now, of course we know that reactive oxygen species (ROS) are nothing to be scoffed at. Any chemist will tell you that having a molecule floating around with an unpaired electron in its outer shell is one of the most dangerous situations a stable local environment can find oneself in. First contact will be the last contact: ROS will bind to its first victim molecule and disrupt the functionality of said molecule. Add several of those angry scavengers and you are certainly in trouble.

Of course, not all is black and white. Some believe that free radicals and ROS under certain conditions can be beneficial to the organism and its longevity. Nothing is yet certain, but the field is certainly not stuck in a blissful state of complete understanding.

Returning to the issue at hand, all would seem at least somewhat logical that by inducing hydroxyl radical production antibiotics clearly contribute to them destroying bacteria. However an aforementioned study in Science refutes this notion.

Researchers claim that they

"found no correlation between an individual cell's probability of survival in the presence of antibiotic and its level of ROS".

 By using a compound, thiourea, an "ROS quencher" they

"protected cells from antibiotics present at low concentrations, but the effect was observed under anaerobic conditions as well".

Since ROS are produced by aerobic respiration, the ability of an ROS quencher to protect bacteria from antibiotics in anaerobic conditions in which ROS cannot be produced indicates that ROS cannot be the deciding factor of bactericidal action.

To be even more sure, they marked cells with a fluorescent tag which showed ROS, separated those cells with highest amount of fluorescence (therefore, highest amount of ROS) from the lowest ones and both populations suffered equivalent cell death upon being bathed in antibiotics.

So the researchers concluded that

"There was essentially no difference in survival of bacteria treated with various antibiotics under aerobic or anaerobic conditions" and thus "this suggests that ROS do not play a role in killing of bacterial pathogens by antibiotics".

With this notion of general mechanism by which antibacterials operate severely damaged, we return to viewing each class as different. Some inhibit the synthesis of cell walls (beta-lactams like penicillin), others dampen the synthesis of nucleic acids (fluoroquinolones), proteins (tetracyclines), act as anti-metabolites (folate pathway inhibitors: sulfonamides) or disrupt membrane function (cyclic lipopeptides: daptomycin).

There is yet much to be said about antibiotics, most pressingly their overuse. Ever increasing bacterial resistance to antibiotics is one of the most pressing matters to be solved. This is exemplified by the recent "nightmare bacteria" which is spreading across US hospitals and is resistant to most powerful antibiotics. More importantly, it kills half of those it infects. Dr. Marc Siegel vocalizes the seriousness of this situation: ""To see bacteria that are resistant is worrisome, because this group of bacteria are very common. The more you use an antibiotic, the more resistance is going to emerge. This is an indictment of the overuse of this class of antibiotic [carbapenems]."

There is a growing awareness and desire to cut back on needless antibiotic usage among an increasing number of people. A piece in The Atlantic has one such anti-antibiotic enthusiast who may just be going a bit too far ("our 14-year-old son had never taken antibiotics"), but at least it shows an increase in understanding that an overly runny nose or a mild fever does not require an onslaught of broad-spectrum antibiotics.

One especially crucial point was made:

"Antibiotics are unnecessary for colds or bronchitis, even when they last longer than two weeks.  Colds and bronchitis often take more than two weeks to resolve, so if there are no signs of pneumonia, then antibiotics can be withheld safely."

Antibiotics are used each and every day and everyone has a general understanding of what they do. In spite of this they remain elusive and still baffle some researchers. They are useful and crucial for keeping the society healthy, however our need to shorten the duration of even the mildest of discomforts can lead to our inability to protect ourselves when the real enemy emerges.


References:

1. I. Keren, Y. Wu, J. Inocencio, L. R. Mulcahy, K. Lewis. Killing by Bactericidal Antibiotics Does Not Depend on Reactive Oxygen Species. Science, 2013; 339 (6124): 1213 DOI: 10.1126/science.1232688

2. Michael A. Kohanski, Daniel J. Dwyer, Boris Hayete, Carolyn A. Lawrence, James J. Collins. A Common Mechanism of Cellular Death Induced by Bactericidal Antibiotics. Cell - 7 September 2007 (Vol. 130, Issue 5, pp. 797-810). doi:10.1016/j.cell.2007.06.049

Homeostasis and immunity

For a first blog post I decided to talk about homeostasis, which is a dynamic regulation of a system's internal environment, and the immune system. The usual choices for this topic when talking about humans would be the nervous and endocrine systems, but I wanted to explore what the immune system has to do with maintaining homeostasis. Later posts will examine this relationship more closely, so as to present the topic with an incrementally increasing level of detail.

To begin with, briefly on homeostasis. The term encompasses a huge portion of nature and all of life. It can be thought of as what gives a system the ability to keep itself comfortable despite pressure from the environment.
Wherever we turn our attention, some sense of homeostasis always pops up, especially if you are trying to find it. It is present in cells as they use pumps to maintain a certain ion concentration, it is evident in an organism which protects itself from overheating by evaporating water from the skin, it is noticeable in society as countries try to maintain their independence and survival by diplomatically regulating both domestic and foreign affairs.

No matter where one looks, homeostasis can always be identified by locating the three main components: sensor, integrator and effector. 

First of all, there must always be something that disturbs the system, like a virus which wreaks havoc or has the potential to do so, or an elevation/fall of some vital parameter, like temperature.

The sensor notices that something is wrong and begins the homeostatic process by informing the integrator about the impending doom to the system's stability and ability to function. The integrator decides what is to be done and transmits commands to the effector which reacts accordingly to the stimulus and if everything goes right restores the normal status of a system.

Of course, even though this description implies that homeostatic mechanisms come into action only when a disturbance occurs, actually due to there being a whole lot of different parameters to be maintained, some mechanisms are always in action. For example the mentioned pumps work constantly by making sure that the intracellular fluid contains more potassium and is more negative than the extracelullar fluid which should be more positive and rich in sodium.

Now, the fine line between a sensor, integrator and effector is pretty clear when talking about the nervous and endocrine systems. Dominika Dabrowski has written a nice overview of thermoregulation: when the temperature drops "this stimulates skin cold receptors (increase in their activity) and cools the blood flowing into the skin. These signals are received by both the hypothalamic thermostat and higher cortical centers. The thermostat is also activated by the change in blood temperature. It initiates responses that promote heat gain and inhibits centers that promote heat loss".

We can immediately identify that the skin receptors are the sensors, the hypothalamus and cortical centers are the integrators. What's left are the effectors which respond to the hypothalamus by inducing involuntary muscle contractions (shivering) to produce heat, vasoconstriction to reduce heat loss, etc.

However, in the immune system, things get quite different and actually the mechanism is not so straightforward as mentioned in the general example. Pathogens are not like temperature. Temperature is just a certain value of a property, while various germs are unwelcome guests and their existence is an absolute value: you can either be free of germs, or infected with germs. There is no middle ground.

Therefore, it is not so unexpected to see some variability in the mechanism of homeostasis, even though the goal remains internal stability. There may be some generalized effectors which remove detrimental stimuli without them being sensed previously, and only after this general effector is breached, the sensor picks up the signal and starts a real, initiated response. The sensors could also be the effectors at the same time. Dendritic cells, for example, swallow the pathogens (effector action) and then present the pathogen on their surfaces so that it can be recognized (sensor action).


Talking about generalized effectors, it is obviously beneficial to be able to ward off unwanted micro-guests without expending any energy, or as little as possible. And since the general consensus the body makes is that "either you're me or you're against me" (the failure of following this consensus will be the topic of a later post), the body has barriers - generalized effectors - which block easy entrance of pathogens into the body. The skin envelops the body and wards of weaponless microorganisms, but they can still get inside the body via openings, such as mouth, nose, ears and gain access to sensitive internal environment of the respiratory or gastrointestinal system. However, the body won't be fooled so easily. The mucous membranes which are present in these areas produce mucous secretions, for example nasal mucus in the nasal passages. Mucus traps small particles such as dust, pollen, also bacteria and viruses which in the absence of mucus would be able to easily penetrate into the lower respiratory tract and other sensitive areas. So when you unpleasantly notice that your mucus is greenish or yellowish, realize that this is the first line of defense doing its job and trapping the bacteria or viruses within itself.

Unfortunately, this superficial defense is very limited and not so effective in maintaining homeostasis against any serious foe. That is obvious, since each year millions of people get colds and other sorts of viral, bacterial and fungal infections. Germs, like Rhinovirus, which remain on the periphery of the respiratory and gastrointestinal tracts cause mild infections like the common cold. Others, mainly bacteria, can induce moderate ones: pharyngitis, laryngitis, etc.
Pathogens can also penetrate the skin, for example, with the help of our misfortune of getting a splinter or a bruise. They can travel in company with ectoparasites, like Plasmodium falciparum does with Anopheles mosquitos and when the mosquito tries to get blood it inadvertently allows Plasmodium to enter the bloodstream and causes one of the most detrimental infectious diseases - malaria.

Fortunately, the immune system is not composed solely of the skin and some slimy mucus. Such external barriers represent only one part of the innate immunity, which together with the acquired immunity represent the way that our organism responds to pathogenic stimuli which threaten its homeostatic stability and sometimes its very existence.

So the immune system is directly linked with maintaining homeostasis both constantly, i.e. with a constant presence of barriers to pathogens, and also upon being induced, when those pathogens breach the general defenses and induce sensors to call for reinforcements.