How does an antibiotic work?
Various antibiotics work in different ways. If you think about it, there are several ways that a bacterium could be prevented from growing or living.

• Prevent the bacterial cell wall from forming properly. The cell wall of a bacterium is required to prevent the cell from rupturing. Water flows across semi-permeable membranes into regions where the concentration of salts is higher (inside of a bacterial cell). If the cell wall weren't there, the cell would fill with water to the point that the membrane ruptured.
• Prevent protein synthesis. New proteins, both those involved in structure as well as chemical reactions (enzymes) must be made continuously or the bacterial cell will die. Old proteins are damaged relatively quickly and soon cease to function - also - new proteins are needed for the new cells produced by cell division (bacterial growth).
• Interfere with DNA synthesis. The chromosome of the cell must be replicated continuously in order for cell division to take place. If this process is disrupted, the cells not only cannot increase in number, the cells will die because a fundamental process has been jeopardized.
• Disrupt plasma and/or outer membrane (in the case of Gram-negative bacteria) function. The cell's plasma membrane, made of two layers of fat (lipids) and many different proteins surrounds all of the bacterial cell's contents. With the two exceptions of water and gases that can flow freely back and forth across the membrane, ALL other nutrient constituents required by the cell must enter the cell across the plasma membrane by specific transport proteins. Too, the energy-producing system of many bacteria (the electron transport system) resides within the plasma membrane. Consequently, any disruption of plasma membrane function will kill the cell.

• Prevent the cell wall (made of cross-linked polymers of peptidoglycan) from being formed properly. The beta-lactam antibiotics such as penicillin and penicillin derivatives as well as the cephalosporins, work in this way. Some examples of the penicillin antibiotics are Ampicillin and Methicillin, and the cephalosporin antibiotics, Cefoxitin and Cefoperazone. Vancomycin is another antibiotic, different from the penicillins and cephalosporins, that is also a very important bacterial cell wall synthesis inhibitor.
• Disruption of the ability of bacteria to make proteins (protein synthesis inhibitors). These antibiotics include those known as tetracyclines, examples of which are aureomycin and tetracycline, those known as aminoglycosides, such as streptomycin, and those known as macrolides such as Erythromycin.
• Interfere with chromosome replication, i.e., DNA synthesis. These antibiotics are designed completely in the laboratory and have never been observed to naturally occur. These antibiotics are the quinolones, an example of which is Ciprofloxacin. You may be familiar with this antibiotic and its use to kill the bacteria responsible for the disease known as anthrax. Note: discuss with your health care provider the risk of possible tendon impairment (or rupture) when taking a quinolone antiibotic).
• Bacterial membrane disruption antibiotics also exist, but cannot be taken internally by humans. Our cell membranes are very similar to bacterial cell membranes. Thus, disruption of the bacterial plasma membrane will also disrupt the plasma membrane of our own cells. Such antibiotics, an example of which is Polymyxin B, will be found in creams and/or ointments and are for topical (surface of skin) use, only.
• Interference with fundamental metabolism - the overall chemical systems in bacteria. These antibiotics are things like the sulfa drugs, an example of which is sulfanilamide. Another metabolism inhibitor is Trimethoprim. These kinds of antibiotics interfere with metabolic processes that bacteria alone, possess.

• The bacterium may have a system that prevents entry of the antibiotic into the cell.
• The bacterium may have a system that destroys the antibiotic if the antibiotic gains entry into the cell.
• The bacterium may have a system that chemically binds with the antibiotic inside the cell and therefore blocks the action of the antibiotic.
• The bacterium may have a system that pumps the antibiotic out of the cell before the antibiotic can act within the cell.

How is antibiotic resistance acquired?
In the absence of human involvement, bacteria in the wild do not usually have resistance to antibiotics. In order for a bacterium to gain resistance to a given antibiotic, there must be either a natural mutation in a gene within the bacterial chromosome (less common), or, the system that leads to resistance must be acquired. Acquisition of antibiotic resistance occurs when genetic material is taken up by the bacterial cell and either incorporated into the chromosome, or, that is able to exist in a stable form independent of the chromosome. Such stable genetic elements that not only exist but that can replicate independently of the chromosome, are known as plasmids. If the genetic information encoded by a plasmid leads to resistance against a particular antibiotic, this plasmid is known as a resistance plasmid. The bacterium that acquired the new genetic information that leads to resistance, is now known as an antibiotic-resistant strain of that bacterial species. Examples of such bacterial strains include Vancomycin Resistant enterococci (VRE) and Methicillin Resistant Staphylococcus aureus (MRSA). By the way, VRE and MRSA are both abbreviations, not acronyms. An acronym is a special form of an abbreviation that spells a word, e.g., such as an APACHE score obtained upon hospital admittance.

If one cell of a bacterial species is resistant to a given antibiotic, are all bacterial cells of that species resistant to the same antibiotic?
No; only that strain and subsequent offspring of that strain will be resistant to that antibiotic. For example, if a bacterial cell acquires a system that destroys penicillin or methicillin, all other cells of that species may still be sensitive to the killing action of the antibiotic. However, the cell that acquired resistance to methicillin will usually be able to pass on this resistance in the form of stable genetic information to all of the progeny of that one cell. Since bacterial cells may divide every 20 minutes, in a very short time there can be many, many cells of the new, resistant strain that will no longer be killed by methicillin.

What difference does it make if a bacterial cell or two acquires antibiotic resistance?
The overwhelming majority of bacteria are not only helpful to us but necessary for our good health. This preponderance of good bacteria means that there are fewer spaces on our body or within our digestive tract available for harmful (pathogenic - disease causing) bacteria to occupy. And, there is enormous competition for the limited nutrients available. Consequently, it's tough for bad bacteria to gain a foothold and to exist in large numbers - special conditions must usually occur in order for such a thing to happen. One such special condition is the loss of competition for space and food. Since antibiotics kill both good and bad bacteria alike, if there is a disease-causing bacterial cell that happens to be resistant to an antibiotic, and most of the good bacteria are killed - this antibiotic resistant bad bacterium now has a significantly better competitive advantage. This strain may now increase in number, gain a foothold and cause disease - and all members of this strain will be resistant to at least one antibiotic that could kill them, to boot.

Under what conditions do bacteria most easily acquire resistance to a given antibiotic?
When bacteria are in a limited geographic environment with routine, consistent exposure to antibiotics - such as a hospital - or within a single individual on long-term antibiotic therapy - or within farm animals treated with low, non-therapeutic doses of antibiotics for weight gain. If antibiotics are used extensively, there is an increased likelihood of selection of a bacterial cell that is resistant to the effects of a given antibiotic. Look at it this way - if there were 100 people in a room and only one individual had an umbrella, spraying water from the ceiling would select that one person for dryness - resistance to getting wet. If this person and their umbrella divided every 20 minutes, soon, the room would be filled only with individuals who had umbrellas and all could remain dry. That individual would represent a strain of bacterium, resistant to an antibiotic, and allowed to increase in number and to perhaps become the predominant occupant of the room.

Another situation that encourages selection for antibiotic resistance is indiscriminate usage of antibiotics. If an antibiotic isn't needed to treat a disease, such as a disease caused by a virus (antibiotics work only on bacteria), the use of antibiotics in this situation increases the opportunity to select a bacterial strain that is resistant to that antibiotic. One particularly troublesome situation in this area is the routine use by the animal food industry of low, non-therapeutic dosage levels of antibiotics. These antibiotics are either the same or very similar to the antibiotics used for human health.

Non-therapeutic use of antibiotics means that the animals are not treated simply to prevent spread of an on-going disease, but healthy animals are treated to prevent spread of disease and to also increase weight gain. It is not yet understood how low levels of antibiotics cause the animals to gain weight. However, the widespread use in this manner of several different antibiotics is thought to increase the risk of development of antibiotic resistance among bacteria dangerous to human health. Antibiotic-resistant bacteria would have a significantly higher chance under such conditions of being selected as survivors.

Is anyone doing anything about this issue?
There is increasing awareness of what we are doing to increase the presence of antibiotic-resistant strains of disease-causing bacteria - both in the medical community and in the animal food industry. There are many more discussions and recommendations being made that are resulting in less indiscriminate use of antibiotics. However, this issue is a world-wide problem and continuous efforts are being made to reduce this threat to human health. One recent success appears to have occurred in Europe. A recent article in the journal Science attests to the effect of a ban on use of the antibiotic, Avoparcin, in animal feed on the prevalence of antibiotic resistance in human hospital patients (Ferber, Dan (2002) Livestock Feed Ban Preserves Drug's Power. Science, 295:, 27-28. The data for the Science article were presented by Belgian scientists at The Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, 16-19, December 2001, that was sponsored by the American Society for Microbiology.

Studies had shown that bacteria isolated from the intestines of animals that were resistant to Avoparcin were also resistant to Vancomycin. Both of these antibiotics work by preventing the cell wall of bacteria to form properly - without cell wall integrity, bacterial cells will rupture and die. As mentioned above, Vancomycin-resistant enterococci exist and are a significant concern for surgery patients who may become infected with these bacteria. Scientists felt that reduction of the use of Avoparcin among animals might eventually reduce the prevalence of Vancomycin resistant bacteria among humans.

The concern that antibiotics in animal feed could eventually select for antibiotic resistant bacterial strains, and that these strains could enter the human intestines through the food chain, caused the European Union to reach an important decision - that is, to ban in 1997 any further use of Avoparcin in livestock feed. Researchers in Europe have been monitoring the effects of this ban. Since the ban was instituted a significant decrease in Vancomycin-resistant enterococci has been observed in bacteria isolated from chickens, pigs and in chicken meat in stores. Perhaps most importantly, in an Antwerp, Belgium hospital patient study in June, 2001, an approximate ten-fold decrease in Vancomycin resistant enterococci were observed relative to when the ban was begun. Since the use of Vancomycin in Belgian hospitals had not changed since 1997, this decrease in Vancomycin resistance appears to be clearly associated with the decrease in use of the similar antibiotic, Avoparcin, in farm animals. In the United States, the U.S. Food and Drug Administration (FDA) has recommended that two different antibiotics, penicillin and tetracyclines be banned from use in subtherapeutic levels in livestock feed. Unfortunately, an appeals court reversed lower court decisions that banned antibiotic use in animal feed, the result of which allows continued use and a contiuation of potential harm to public health. See: Appeals Court Rules FDA Not Required to Hold Hearings on Antiobiotic Use in Animals. It is estimated that approximately 80% of all antiibotics administered within the United States was for domestic animal use.

You may wish to read additional articles associated with this topic.

• What the Heck is an Antibiotic?
• What the Heck is Penicillin?
• What the Heck is a Gene?
• What the Heck is an E. coli
• American Society for Microbiology's Web Site

Book: Don't Touch That Doorknob!

Copyright John C. Brown, January, 2002

Updated September 8, 2014
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