"The Lord hath created medicines out of the earth; and he that is wise will not abhor them." Ecclesiasticus, xxxviii. (King James Bible Apocrypha)
So began the Nobel Prize acceptance speech of Selman Waksman who first used the term “antibiotic” and discovered streptomycin, the breakthrough tuberculosis treatment. Indeed, Waksman and others isolated lifesaving microbe-killing compounds produced in nature by fungi and bacteria in the soil.
Traditional thought in the biomedical community maintained that natural antibiotics were a kind of microbial weaponry, elicited to stave off competing organisms. With an idea shift worthy of a Copernican turn, now microbiologists assert that antibiotics may serve another purpose, more in line as intermicrobial signals or tools of communication, necessary for basic physiological processes and homeostasis. The change in perception has implications not only in understanding microorganisms, but also for the future development of antibacterial agents and combating antibiotic resistance.
For the last sixty-plus years, antibiotics have been the wonder drugs, saving countless lives in the fight against infectious diseases caused by bacteria. Many chemicals, for example, cyanide, are lethal to bacteria, but they cannot be used as treatments because they kill the host as well. Natural antibiotics like penicillin as well as semi-synthetic and synthetic products such as cephalosporins and sulfa drugs, respectively, destroy bacteria or inhibit growth at low concentrations without substantially harming the host. However, along with the discovery and the use of antibiotics have come the emergence and spread of drug resistance as more and more bacteria acquire protection from one or multiple antibiotics to which they were formerly susceptible.
An example is methicillin-resistant Staphylococcus aureus (MRSA), which are strains of the bacterium resistant to methicillin and related antibiotics (e.g. penicillin and cephalosporin). Some MRSA are also resistant to vancomycin, the antibiotic used most widely in treating infections due to MRSA. In fact, the number of people who die from MRSA infection exceeds the deaths from acquired immunodeficiency syndrome (AIDS) in the U.S.
Penicillin resistance was discovered prior to the clinical use of the antibiotic. Bacteria develop antibiotic resistance through two main mechanisms: changes in the DNA sequence (mutation) or by gene transfer from other bacteria already resistant to the antibiotic (horizontal gene transfer, HGT). HGT allows resistance genes to spread easily from one bacterium to another. The genes confer modes of resistance that include chemical modification of the antibiotic, inactivation through physical removal from the cell, or modification of the target site so recognition by the antibiotic is no longer possible. For the most part, antibiotic resistance genes have originated in environmental or soil bacteria, begging the question: What is the role of antibiotics and antibiotic resistance in the natural environment or ecosystems?
Recent evidence suggests that in nature antibiotic-producing organisms evolved to coordinate biological activities among community members, for instance, to facilitate the multiplication of microorganisms in a specific environment, to function in the general elimination of toxic substances generated from metabolism, or in providing food. Linares et al. demonstrated that at low concentrations, antibiotics exhibit different effects than they do at high concentrations, such as changes in the expression of several genes, which in turn may affect many bacterial properties. These different effects corresponding to high or low concentrations of the substance are consistent with antibiotics having a biological function other than defense.
The findings of a study published in the February 12th issue of the journal Molecular Cell correlate with the new thinking concerning antibiotics and antibiotic resistance. Howard Hughes Medical Institute investigator, James J. Collins and his team at Boston University determined that high concentrations of antibiotic can lead to an increase in reactive oxygen species (ROS), which form as a natural byproduct of the normal metabolism of oxygen and are lethal to bacteria. Contrastingly, when the level of antibiotic is low and less than lethal, the same reaction causes changes in the genetic material (mutations) that the bacteria not only survive, but also protects them from other antibiotics beyond the one to which they were exposed. The research has importance implications for administration and compliance with antibiotic treatment as well as the development of new antibiotics enhanced with compounds that may prevent multi-drug resistance.
References and Read-more-about-it:
1. Kohanski MA, Depristo MA, Collins JJ. Sublethal Antibiotic Treatment Leads to Multidrug Resistance via Radical-Induced Mutagenesis. Mol Cell. 2010 Feb 12; 37(3):311-320.
2. Jayaraman R. Antibiotic resistance: an overview of mechanisms and a paradigm shift. Current Science
2009 June 10; 96 (11):1475-1484. Review
3. Martinez JL. The role of natural environments in the evolution of resistance traits in pathogenic bacteria. Proc Biol Sci. 2009 Jul 22;276(1667):2521-30. Review
4. Mlot C. Antibiotics in Nature: Beyond Biological Weapons. Science. 2009 June 26; 324:1637-1639.
5. Linares JF, Gustafsson I, Baquero F, Martinez JL. Antibiotics as intermicrobial signaling agents instead of weapons. Proc Natl Acad Sci U S A. 2006 Dec 19; 103(51):19484-9.
6. Todar K. Todar’s Online Textbook of Bacteriology. Bacterial resistance to antibiotics. Available at: http://www.textbookofbacteriology.net/resantimicrobial.html. Accessed February 22, 2010.
7. Seele M. Medical News Today. Low Levels of Antibiotics Cause Multidrug Resistance in 'Superbugs'. Available at: http://www.medicalnewstoday.com/articles/179045.php. Accessed February 22, 2010.
8. American Chemical Society. National Historic Chemical Landmarks. Selman Waksman and Antibiotics. Available at: http://acswebcontent.acs.org/landmarks/antibiotics/antibiotics.html
Accessed February 22, 2010.