Bacteria, Antibiotics, and the Evolution of Antibiotic-Resistance

Although we can't see them, bacteria are everywhere - living on almost every surface, in the soil (one gram of surface soil contains more than 100 million bacteria), and even in some of the harshest environments on earth (e.g., sulfur pools and near-boiling undersea hydrothermal vents). They play a critical role in our ecosystem, carrying out essential processes such as nitrogen fixation and participating in symbiotic relationships with other organisms that cause no harm to the host. Disruption of the delicate interplay between bacteria and their environment is potentially very dangerous to the health and well-being of all organisms. Consider the bacteria Staphylococcus aureus. Normally, this species lives in the human oropharynx, nose, large intestine, vagina, and on the skin without causing harm. However, if a breach in the skin or mucosal barrier occurs, S. aureus gains access to nearby tissues or the bloodstream where it can colonize and cause disease. The relationship between S. aureus and its human host, then, is dynamic in nature, capable of quickly shifting from mutualistic or commensualistic to parasitic.

The search for ways to eliminate diseases caused by bacteria led to the discovery of antibiotics. These drugs kill or inhibit the growth of susceptible bacteria. When antibiotics became widely available in the 1940s they were hailed as miracle drugs - able to cure diseases and not just reduce their symptoms. However, as early as 1950 strains of bacteria emerged that were resistant to all standard antibiotics. This problem, which has only intensified in severity since the 1950s, demonstrates the biological principle of natural selection. As antibiotic use increases, natural variants of bacteria able to resist antibiotics survive longer than antibiotic susceptible bacteria, their progeny become more numerous, and the pool of antibiotic resistance genes grows. Since bacteria easily exchange genetic information with each other, resistance genes are passed between species, genera, and families of bacteria. Today, several species of bacteria capable of causing life-threatening diseases are able to withstand exposure to every available antibiotic, creating an antibiotic resistance crisis.

Antibiotics: Range of Effectiveness and Mechanisms of Action

The effectiveness of antibiotics in ameliorating disease depends on two factors:

1. Spectrum. The spectrum of an antibiotic refers to the diversity of bacteria against which an antibiotic acts. Bacteria are typically classified as gram positive (e.g., S. aureus) or gram negative (e.g., Escherichia coli). Gram staining is a procedure in which bacteria are exposed to crystal violet dye, washed, and then exposed to a counter-dye. Gram positive bacteria retain the crystal violet dye while gram negative bacteria do not. Other bacteria do not fit neatly into the gram positive/gram negative classification scheme. These include classes of bacteria like mycobacteria, rickettsia, and chlamydia. Generally, narrow spectrum antibiotics act against one class of bacteria while broad spectrum antibiotics act against more than one class of bacteria. Table 1 shows the spectrum of several antibiotics.
2. Selective toxicity. Selective toxicity is a measure of the degree to which an antibiotic is harmful to bacteria but not the bacterial host. Antibiotics with high selective toxicity disrupt enzymes or structures that are unique to bacteria; antibiotics with low selective toxicity inhibit the same process in bacteria as in host cells, or damage host cells in some other way. Table 1 shows the selective toxicity of various antibiotics as well as the cellular processes they disrupt.

Table 1. Common antibiotics and some of their characteristics.

Cefazolin is an example of a broad spectrum antibiotic that functions by blocking bacterial cell wall synthesis. Bacterial cell walls, which maintain osmotic balance and provide an added layer of protection against toxic substances, are made up of a typical plasma membrane as well as additional specialized structures like the peptidoglycan (Figure 1). In gram positive bacteria, a series of enzymes that includes transglycosylase and transpeptidase catalyzes cell wall formation; cefazolin binds to and inhibits transpeptidase (Figure 2). Since animal cells do not possess cell walls, cefazolin has a high selective toxicity. Several strains of bacteria have emerged that are resistant to all cefazolin-related antibiotics (including methicillin and penicillin) and are referred to as MRSA (Methicillin resistant S. aureus). Resistance to cefazolin-related antibiotics is usually conferred by the chromosomal gene mecA. MecA encodes a protein that binds to and sequesters these antibiotics, preventing them from inhibiting transpeptidase (Figure 2). The most common MRSA strain is hospital-acquired MRSA which is also resistant to many other common antibiotics (e.g. tetracycline, Bactrim).

Over the next week and a half you will be examining the problem of antibiotic resistance. In seminar, you will walk in the steps of Dr. Jenna Collins as she attempts to prescribe the appropriate antibiotic to her seriously ill pediatric patient. In lab, you will take an experimental approach to the problem by surveying for the prevalence of antibiotic resistant bacteria carried by you and your peers and residing in nearby water supplies. Finally, you will work with a group of students in your section to summarize the results from your lab and discuss some of the insights you've gained about this global problem.

References

• Baquero, F. and Blazquez, J. 1997. Evolution of antibiotic resistance. Tree 12(12): 482-487.
• Coppoc, G. L. 10/10/99. Chemotherapy: Drug Groups. http://www.vet.purdue.edu/bms/courses/mcmp611/chmrx/chmrxtit.htm.
• Clinical Pharmacology Online. http://www.cp.gsm.com/. Tampa: Gold Standard Multimedia Inc.
• Levy, S. B. 1998. The challenge of antibiotic resistance. Scientific American 278(3): 46-53.
• Prescott, L. M., Harley, J. P., and Klein, D. A. Microbiology. Dubuque: Wm. C. Brown Publishers, 1990.
• Walsh, C. Deconstructing vancomycin. 1999. Science 284: 442-443.

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