Antibacterial Drugs

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Antibacterial Drugs

Introduction

Antibacterial drugs stop bacterial infections in two ways: they prevent bacteria from dividing and increasing in number, or they kill the bacteria. The former drugs, which prevent bacteria from increasing in number but do not kill the bacteria, are termed bacteriostatic drugs. The latter, which kill the infectious bacteria, are known as bactericidal drugs. Both types of drugs can stop an infection.

The terms antibacterial drugs and antibiotics are often used interchangeably. Though the most common antibacterial drugs are the many types of antibiotics, other compounds can also be considered antibacterial. One example is alcohol, which kills bacteria by dissolving the cell membrane. Another example is carbolic acid, which was famously used by Joseph Lister (1827–1912) in the mid-nineteenth century as a spray to prevent bacterial contamination of wounds during operations. Antibacterial agents such as alcohol and carbolic acid are more accurately considered disinfectants, chemicals that kill or inactivate bacteria on surfaces and instruments, rather than antibiotics, which are generally taken internally and can create resistant strains of bacteria.

History and Scientific Foundations

The use of antibacterial drugs is ancient. Thousands of years ago, although the scientific basis of infection and its treatment was unknown, infections were sometimes successfully treated with molds and plants. Centuries later, the production of antibiotics by some species of molds and plants was discovered. One argument against the large-scale deforestation of regions, such as the Amazon basin, is that there are likely still many antibiotic-producing molds and plants yet to be discovered.

The antibiotic era began in the first decade of the twentieth century, when Paul Ehrlich (1854–1915) discovered a compound that proved to be an effective treatment for syphilis. In 1928, Sir Alexander Fleming (1881–1955) discovered the antibiotic penicillin. With recognition of the compound's prowess in killing a wide variety of bacteria, interest in antibiotics soared. In 1941, Selman Waksman (1888–1973) coined the term antibiotic. In the ensuing decades, much work focused on the discovery of new antibiotics from natural sources, the laboratory alteration of existing compounds to increase their potency (and, later, to combat the problem of antibiotic resistance), and the synthesis of entirely new antibiotics.

Antibiotics kill bacteria in a variety of ways. Some alter the structure of the bacteria so that the bacteria become structurally weakened and unable to withstand physical stresses, such as pressure, with the result that the bacteria explode. Other antibiotics halt the production of various proteins in a number of ways: inhibiting the decoding of the genes specifying the proteins (transcriptional inhibition); blocking the production of the proteins following the production of the genetic message, messenger ribonucleic acid (mRNA, in a process termed translational inhibition); blocking the movement of the manufactured protein to its final location in the bacterium; or blocking the import of compounds that are crucial to the continued survival of the bacterium.

Some antibiotics—described as broad-spectrum— are effective against many different bacteria. Other anti-biotics—described as narrow-spectrum—are very specific in their action and, as a result, affect fewer bacteria.

Penicillin is the classic example of a class of antibiotics known as beta-lactam antibiotics. The term beta-lactam refers to the ring structure that is the backbone of these antibiotics. Other classes of antibiotics, which are based on the structure and/or the mechanism of action of the antibiotic, are tetracyclines, rifamycins, quinolones, aminoglycosides, and sulphonamides.

Beta-lactam antibiotics kill bacteria by altering the construction of a portion of the bacterial membrane called the peptidoglycan. This component is a thin layer located between the inner and outer membranes of Gram-negative bacteria (an example is Escherichia coli) and a much thicker layer in Gram-positive bacteria (an example is Bacillus anthracis, the bacterium that causes anthrax). The peptidoglycan is a tennis racket-like mesh of sugar molecules and other compounds that is very strong when intact. This network has to expand to accommodate the growth of the bacteria. This is done by introducing breaks in the peptidoglycan so that newly made material can be inserted and incorporated into the existing network, cross-linking the newly inserted material with the older material. Beta-lactam antibiotics disrupt the final cross-linking step by inhibiting the activity of enzymes called penicillin-binding proteins, which are the enzymes that catalyze the cross-linkage. Other enzymes called autolysins also are released. The autolysins degrade the exposed peptidoglycan at the sites that are defectively cross-linked. The result is the weakening of the peptidoglycan layer, which causes the bacterium to essentially self-destruct.

Another class of antibiotics with a mode of action similar to the beta-lactam antibiotics are the cephalosporins. There have been various versions, or generations, of cephalosporins that have improved the ability of these antibiotics to withstand enzyme breakdown. The latest cephalosporins are the fourth generation of these antibiotics.

Aminoglycoside antibiotics bind to certain regions of the cellular structure called ribosomes. Ribosomes are responsible for decoding the information contained in mRNA to produce proteins. By binding to the ribosome, aminoglycoside antibiotics disrupt protein production, which is often lethal for the bacterium.

As an final example, quinolone antibiotics impair an enzyme that unwinds the double helix of deoxyribonucleic acid (DNA). This unwinding must occur so that the genetic information can be used to make proteins and other bacterial components. These antibiotics kill bacteria at the genetic level.

Applications and Research

Every year, antibiotics continue to save millions of lives around the world. In less developed regions, where access to medical care can be limited, campaigns by the World Health Organization (WHO) and other agencies to distribute antibiotics have been invaluable in the response to epidemics of diseases such as cholera, plague, and yellow fever.

The discovery and manufacture of antibiotics continues. Screening of samples to uncover antibacterial properties has been automated; thousands of samples can be processed each day. Furthermore, the increased knowledge of the molecular details of the active sites of antibiotics and the ability to target specific regions have been exploited in the design of new antibiotics.

Impacts and Issues

In the decades after pencillin's discovery and use, many different antibiotics were discovered or synthesized and introduced for use. The control of bacterial infections became so routine that it appeared infectious diseases would become a problem of the past. However, that optimism has proven to be premature. Instead, some bacteria have developed resistance to a number of anti-biotics. For example, bacterial resistance was first observed only about three years after the commercial introduction and widespread use of penicillin in the late 1940s. Penicillin-resistant staphylococcus bacteria were reported in 1944, and, by the 1950s, a penicillin-resistant strain of Staphylococcus aureus became a worldwide problem in hospitals. By the 1960s, most staphylococci were resistant to penicillin. Two decades ago it was rare to encounter methicillin-resistant S. aureus (MRSa). In 2007, MRSa is a daily concern of a hospital's infection control challenge.

WORDS TO KNOW

ANTIBIOTIC: A drug, such as penicillin, used to fight infections caused by bacteria. Antibiotics act only on bacteria and are not effective against viruses.

ANTIBIOTIC RESISTANCE: The ability of bacteria to resist the actions of antibiotic drugs.

BACTERIOCIDAL: Bacteriocidal is a term that refers to the treatment of a bacterium such that the organism is killed. Bacteriostatic refers to a treatment that restricts the ability of the bacterium to grow. A bacteriocidal treatment is always lethal and is also referred to as sterilization.

BACTERIOSTATIC: Bacteriostatic refers to a treatment that restricts the ability of the bacterium to grow.

BROAD-SPECTRUM ANTIBIOTICS: Broad-spectrum antibiotics are drugs that kill a wide range of bacteria rather than just those from a specific family. For, example, Amoxicillin is a broad-spectrum antibiotic that is used against many common illnesses such as ear infections.

DISINFECTANT: Disinfection and the use of chemical disinfectants is one key strategy of infection control. Disinfectants reduce the number of living microorganisms, usually to a level that is considered to be safe for the particular environment. Typically, this entails the destruction of those microbes that are capable of causing disease.

NOSOCOMIAL: A nosocomial infection is an infection that is acquired in a hospital. More precisely, the Centers for Disease Control in Atlanta, Georgia, defines a nosocomial infection as a localized infection or one that is widely spread throughout the body that results from an adverse reaction to an infectious microorganism or toxin that was not present at the time of admission to the hospital.

The effectiveness of an antibiotic to which bacteria have developed resistance can sometimes be restored by slightly modifying a chemical group of antibiotic. For example, the antibiotics ampicillin and amoxicillin are variants of penicillin. However, this strategy usually produces only a short-term benefit, since resistance to the altered antibiotic also develops.

One factor contributing to the growth of antibiotic resistance is the overuse or misuse of antibiotics. All the bacteria responsible for an infection may not be killed if an insufficient concentration of an antibiotic is used or if antibiotic therapy is stopped before the prescription has been used completely. The surviving bacteria may possess resistance to the antibiotic, which can sometimes be passed on to other bacteria. For example, tuberculosis has re-emerged as a significant health problem, especially for people whose immune systems are compromised, since the tuberculosis bacteria have developed resistance to the antibiotics used to treat them.

Acinetobacter baumannii is another bacterium that has developed resistance to many antibiotics. This bacterium is normally found in soil and water, and so is commonly encountered. While Acinetobacter baumannii infections were once confined to hospitals, where they accounted for about 80% of all nosocomial (hospital-acquired) infections, the bacterium now has become a growing problem for the military. Over 200 U.S. soldiers wounded in Iraq since 2003 have developed serious infections caused by multi-resistant A. baumannii, and military physicians have few treatment options for these infections.

New antibacterial drugs are expected to produce blockbuster sales for their manufacturers, as emerging resistant organisms push the development of new and efficient antibiotics into the forefront.

BIBLIOGRAPHY

Books

Bankston, John. Joseph Lister and the Story of Antiseptics. Hockessin, DE: Mitchell Lane Publishers, 2004.

Levy, Stuart B. The Antibiotic Paradox: How the Misuse of Antibiotics Destroys Their Curative Powers. New York: Harper Collins, 2002.

Thompson, Kimberly, and Debra Fulghum. Overkill: Repairing the Damage Caused by Our Unhealthy Obsession with Germs, Antibiotics, and Antibacterial Products. New York: Rodale Books, 2002.

Walsh, Christopher. Antibiotics: Actions, Origins, Resistance. Herndon, VA: ASM Press, 2003.

Brian Hoyle

Infectious Diseases: In Context