Bacterial Resistance to Antibiotics – How does it Occur?

Although the emergence of bacterial antibiotic resistance has concerned those involved in public health for many years, the mechanism for this resistance is still poorly understood.  The magnitude of this problem is compounded by the global spread of the infectious agents that cause such diseases as gonorrhea and tuberculosis and that have become resistance to a broad spectrum of antibiotics.

Dr. Qiucen Zhang from the Department of Physics at Princeton University in a collaborative effort with others at various institutions has attempted to define the variables and quantify the nature of the development of bacterial immunity to antibiotics.

In previous work, resistant mutations in bacterial populations have been isolated and their genetic makeup successfully analyzed.  However, Zhang and his colleagues sought to understand how such mutations actually occur and spread within a given bacterial population when it is first subjected to antibiotics.

In order to elucidate this process, it was important to simulate the micro-environment that is present in nature – within a host organism, for example.  The candidate organism that was chosen for this study was Escherichia coli, a ubiquitous bacterial species.  A device was constructed for this purpose was designed to mimic a normal bacterial niche.  The antibiotic that was chosen for this study was ciprofloxacin, often used in a clinical setting.  This substance inhibits DNA replication and cell division but does not kill the bacterial cell target.

The findings from these experiments were that resistance of Escherichia coli to ciprofloxacin occurred within a mere ten hours of the introduction of the drug, and with as few as 100 bacteria.  In addition, DNA analysis of the resistant strain showed four unique single-nucleotide polymorphisms (SNPs) that could account for the antibiotic resistance.

These results are of immense importance in that they help elucidate the often rapid appearance of antibiotic resistance with the body of mammals, including humans.  These data may also be of used in improving the understanding of the emergence of drug resistance in patients undergoing cancer chemotherapy.    

Meteorites and Prebiotic Organic Matter

It has been long understood that in the early history of the earth before the appearance of life, there were present organic substances that were the precursors to the complex compounds that are the essential ingredients for all living things.  These molecular precursors are referred to as prebiotic organic matter.  In addition, the cosmological data has established that the earth along with all the other planetary bodies within our solar system were formed from material expelled from the sun during its formation – the so-called “protoplanetary disk.”

A fundamental question that arises from these known occurrences is the actual origin of prebiotic organic matter.  One of the possible answers to this question is that these materials may have been seeded as a result of collisions of meteorites on the earth’s surface.  This postulate is made even more plausible if one takes into account the fact that in the early history of the planet collisions with meteorites were exceeding common.

Of particular interest is a class of meteorites referred to as the carbonaceous chondrite meteors that are believed to be samples of primitive meteorites that contain the material that was part of the formation of planet earth some 4.6 billion years ago.  These generally consist of insoluble organic matter (IOM) and soluble organic matter ((SOM). 

Dr. Christopher D. K. Herd from the Department of Earth and Atmospheric Sciences at the University of Albert, Canada and his colleagues systematically analyzed the Tagish Lake – in the Southwest region of the Yukon in Canada - meteorite specimens that fell on the frozen lake and were harvested within a few days.  The freshness of the samples effectively ruled out the possibility of contamination from the local environment – an issue that is always of major concern in these types of studies.  The investigative group chose four samples for detailed evaluation. 

Their findings were of extreme interest, for they discovered that the water extracts from these samples were dominated by monocarboxylic acids (MCAs) including formic and acetic acids that play key and ubiquitous roles in the biochemical metabolism of life on the planet.  They isolated eleven different examples of this class of organic compound.  In addition to these, amino acids were also identified.  Amino acids are the basic building blocks from which all proteins are constructed.  The evidence that was accumulated in these studies supports an extraterrestrial origin for these compounds.

This conclusion, if true, is of immense value in understanding the evolution of life on planet earth as well as encouraging speculation as to the possibility of life on other worlds or so-called “exoplanets.”

Snowpack Declines in North America

The levels of snowpack in the mountains in the Western United States have a substantial impact upon the local natural environment.   This is due to the fact that increased runoff impacts temperature due to the loss of capacity of snow and ice to reflect heat back into the atmosphere – the so-called "albedo feedback."  This in turn influences a wide range of ecosystem processes.

It has been reported that snowpack in the Western United States has experienced a noticeable decline in recent decades.  Weather projections predict that this decline will continue to increase in the twenty-first century.  In order to quantify these changes Dr. Gregory T. Pederson and his colleagues from the U.S Geological Survey (USGS) at the Northern Rocky Mountain Science Center in Bozeman, Montana have developed snowpack reconstructions for the headwaters of the Columbia, Missouri and Colorado Rivers.  These reconstructions examine levels of snowpack that span from five hundred to a thousand years.  These findings are based upon an "extensive network of tree-ring sites," and elucidate patterns of water management and snow accumulations over extended periods of time.  The study of tree-rings has long been utilized to reconstruct patterns in regard to precipitation, drought and temperature.  Previous studies have clearly demonstrated that the amount of water available to trees during their growing cycle is largely dependent on the amount of snowpack that accumulated during prior winter seasons.

As a result of the data accumulated during this investigation, the author concluded that, "Over the past millennium, late 20^th century snowpack reductions are almost unprecedented in magnitude across the northern Rocky Mountains."   This is a matter of serious concern in that it may well be a harbinger of future conditions of drought and establishes further relationships between the accumulation of greenhouse gases in the atmosphere, temperature and the global water cycle. 

The Role of the Human Immune System in Obesity

Human immunity has developed, over evolutionary time, into a complex system that impacts a great deal of human biology.  It is for this reason that it often a key player in the cause of many ailments.  It has recently been implicated in human obesity, insulin resistance and type 2 diabetes – these three conditions constitute the so-called metabolic syndrome.  Immune responses are potent reactions to bodily insults and, therefore, must be tightly regulated.  These responses are activated and suppressed by a large family of small regulatory proteins referred to as interleukins.

The white blood cells (WBC) that are found circulating in human blood are, in fact, comprised of a complex mixture of cell types that all perform unique immunological roles.  Eosinophils are a particular WBC type that is classically involved in combating helminth (parasitic worm) infections and allergies.  In addition, macrophages are a subtype of WBC that is characterized by its large size and ability to respond to a wide range of human infections. 

Extensive studies of obesity using animal models led by Dr. Davina Wu at the Howard Hughes Medical Institute at the University of California in San Francisco have implicated Eosinophils and a particular subtype of macrophage referred to as alternatively activated macrophages (AAMs) in the maintenance of glucose balance in fat (Adipose) tissue.  It appears that the role of eosinophils in this process involves the secretion of a type of Interleukin called Interleukin-4 (IL-4).  When eosinophils are not present in adipose tissue, the level of glucose is no longer subject to regulation.

Doctor Wu and colleagues, working with the mouse model, have shown that the macrophages resident in the adipose tissue of obese subjects are actively involved in an inflammatory response while the macrophages in the adipose tissue of lean mice are not.

This study reinforces the established relationship between metabolism and immunity.  Furthermore, these findings support the connection between obesity and the enrichment of those genes involved in inflammatory and immune responses in humans – a strong indication of the health dangers posed by obesity. 

A New Approach to Immunization Against the Flu Virus

Influenza – the flu – continues to infect millions of individuals each year and cause thousands of deaths.  In addition, the economic losses associated with this illness are considerable.  Although immunizations against this virus exist, their effectiveness is diminished by the fact that this virus mutates readily and produces a variety of strains that evade the immunization strategy.  These vaccines provide only limited protection against these strains.  In order to more fully understand the nature of the global health problems posed by the influenza virus, we will examine the nature of its action.

 

The influenza virus is essentially spherical in shape.  Its outer layer is, in fact, a lipid membrane that it has acquired from the host cell that it has previously infected.  Embedded in this outer layer are proteins that are characteristic of the strain of the virus.  It is these proteins that are potential targets for antibodies used in various vaccine regimens.   The virus – like all viruses – is essentially inert outside of living cells.  Once it effectively infects a target tissue – usually in the respiratory system –the virus delivers the infective material directly into the target cell.  The influenza virus belongs to a class of viruses called Ribonucleic acid (RNA) viruses; because, RNA is the infective agent.  Once the viral RNA enters the cell, it commandeers the cell machinery to produce more viruses and eventually kill the cell.  The dead cell releases its contents including many copies of the virus and each of these goes on to infect neighboring cells.

The strategy behind the development of vaccines against this virus is to discover an identifying protein on the virus' surface that persists (highly conserved) over a wide variety of subtypes.  This has proved to be a very elusive quest.   However, there has been a recent discovery of what is referred to as V_H1-69 antibodies that knock out almost all type A Group 1 viruses.  This is an exciting development in its own right, since it is the type A virus that represents the most virulent strain.

One of the major surface proteins on the Influenza virus is Hemagglutinin (HA).   Antibodies that target HA, for example, bind with a unique part of the protein referred to as an antigenic determinant or epitope.  Doctor Damian C. Ekiert and his colleagues from the Department of Molecular Biology at the Scripps Research Institute in LaJolla California have isolated and characterized a human monoclonal antibody called CR8020 that has been shown to have broad reactivity to most group Type A 2 viruses.  It seems quite possible that a cocktail containing these two antibodies -  VH1-69  and CR8020 - may produce an effective universal flu vaccine.  This would be an exciting development from the global public health perspective.

A Potentially New Therapy for Chagas Disease, a Parasitic Infection

Chagas disease is the result of an infection caused by the parasite, Trypanosoma cruzi.  The vector for this parasite is the so-called assassin bug or kissing bug that targets its hosts for blood, usually at night.  The parasite is usually transmitted through the insect's feces.  Millions of people in Latin America carry this parasite.  In addition, the United States and Spain have reported the highest incidences of this disease outside of Latin America.  Furthermore, the World Health Organization (WTO) has estimated that ten million people worldwide are infected with this parasite. 

 

The symptoms are somewhat benign at the early stages of infection.  Unfortunately, the parasite persists within the body for years or decades and can ultimately lead to serious damage to the heart, often resulting in death.

 

The current drugs available to treat this disease – nifurtimox and benznidazole - are outdated and of little value.  In addition to their serious side effects, their efficacy depends upon a 60 to 90 day course of treatment – this requirement makes their use highly impractical. 

 

In regards to the etiology of the disease, there is a crucial enzyme, cruzain, that is a necessary component in the life cycle of Trypanosoma cruzi.  Cruzain belongs to a class of enzymes referred to as proteases – enzymes that catalyze the degradation of proteins.  Doctor James McKerrow, a biochemist at the University of California, was in search of a suitable inhibitor of this enzyme.  He enlisted the help of his colleague Doctor Jim Palmer, a chemist who had synthesized a number of protease inhibitors when he was at Khepri Pharmaceuticals in San Francisco.  In response to this request, Palmer synthesized a potent version of an inhibitor that effectively led to the death of the parasites grown in the laboratory.

 

This is an exciting development that has captured the attention of the Food and Drug Administration (FDA) that has approved a phase I safety trial of the compound referred to as K777.

The Waste of Human Potential

Every day, within the human world, there is the regrettable and apparently inexorable waste of human potential.  Every day, countless numbers of individuals die from the starvation not because there is a scarcity of food, but because they do not have access to the abundance that does exist.  Everyday large numbers of humans die from diseases and conditions that are preventable, treatable and, in some cases, curable, only because they lack the resources to gain access to the wondrous medical advances that exist in the larger world.  Every day, tens of millions of children are denied access to meaningful educational resources; the net effect of this reality is that these children will never realize the wondrous gifts that they possess.  Instead, they will be relegated to a future in which their primary behavior will be directed towards survival in a world that apparently rejects their possible contributions to the larger society.  Every day, millions upon millions of human beings are without a place of shelter to which they can retreat from the relentless onslaught of their daily lives.  Every day, the natural environment worsens as human societies continue to pursue reckless and short-sided policies that suggest a grim future for the species.

Contemporary humans are living a tragedy that is wholly preventable.  There is no legitimate reason why any individual cannot have access to all the necessities required for a meaningful life.  There is no reasonable explanation for the barbaric conditions in which so many live.  There is no rational discourse that can abide the miserable fate of so many of the human kind other than the belief that only a few of us are deserving and the rest are the castoffs in the pursuit of wealth and power.

The pathetic aspect of the human condition is that we can be the architects of a very different world – a world that can not only sustain human life, but also enrich the lives of all of us, everywhere.