Drug Resistance

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ORIGINS OF ANTIBIOTICS Accidents in science occasionally lead to great discoveries. We owe the identification of penicillin to one such serendipitous mishap. Sir Alexander Fleming discovered the first therapeutic antibiotic in 1929 when a green mold contaminated one of his bacterial culture dishes. Fleming observed that where the mold had invaded, the bacterial colonies ( Staphylococcus aureus) had disappeared. He realized that not only did this mold—which was of Penicillium notation—have antibacterial properties in vitro, but that there was also potential for using the mold’s secretions in therapies. How did the mold get into the dish in the first place? As it turns out, Fleming’s lab was upstairs from the lab of a mycologist, and the mold from the mycologist’s lab contaminated Fleming's cultures. Although scientists try hard not to contaminate each other’s work, their fortunate failure to do so in this instance led to a discovery that saved millions of lives. Actually, Fleming was not the first person to recognize the antibacterial properties of mold. As far back as 2,500 years ago, the Chinese were using treatments made of moldy soybean curd to treat infections. The ancient Egyptians rubbed moldy bread on wounds to cure them, and moldy cheese was used for the same purpose in parts of Europe. BACKGROUND These days, you’re not going to scrape the mold off cheese to procure its antibiotic effects. Myriad antibiotics are available to treat various illnesses, curing bacterial infections ranging from strep throat to urinary tract infections. The structure of the cell wall divides bacteria into two groups, the Gram positive and the Gram negative. Gram-positive bacteria have a thick layer of peptidoglycan, a sugar and peptide coating that gives a cell its shape and helps it stay intact. The original antibiotic, penicillin, and its cousins are used to treat infections caused by bacteria that are “Gram positive.” Gram-positive bacteria stain blue-violet in a Gram-staining procedure. Streptococcal and staphylococcalstrains are Gram positive, and these bacteria are responsible for illnesses such as strep throat, blood poisoning, pneumonia, and toxic shock syndrome. Other classes of antibiotics, including streptomycins and tetracycline, effectively destroy both Gram-negative and Gram-positive bacteria, making them able to fight pathogens such as Shigella or Salmonella. BACTERIAL RESISTANCE AND HEALTH Many bacterial strains now resist the effects of antibiotics that once could destroy them. Every population of bacteria may have some individuals that

are resistant. The proliferation of antibiotics and careless use of the drugs have given some resistant bacteria the upper hand in the fight against disease. A patient who is prescribed a 10-day course of antibiotics, but who quits taking them after a couple of days because the symptoms have subsided, leaves behind bacteria that resisted the antibiotic effect. Growth of these bacteria may have slowed in the presence of the antibiotic, but the bacteria are not completely wiped out. Some resistant bacteria may survive an even longer course of antibiotics if the dosage of the drug is not high enough. Typically, after a complete, full-strength antibiotic course, so few resistant bacteria remain that the body’s own immune system can handle them; however, a short course may leave behind so many resistant bacteria that they proliferate. These resistant bacteria also have a better chance to flourish because the other, weaker, bacteria have died. It’s the scenario for a medical crisis. HISTORY OF DEVELOPMENT OF RESISTANCE Resistant bacteria have always been around and existed long before humans began using antibiotics therapeutically. What is new in the world of resistance is how quickly new resistant strains arise. The widespread use and misuse of antibiotics contribute to the problem. For the first time in decades, people in theUnited States are dying of bacterial infections that cannot be treated.

Right after we began using penicillin, some Staphylococcus strains were identified as resistant to it. o Today, 80 percent of Staphylococcus strains do not respond to penicillin. In the 1940s and early 1950s, streptomycin, chloramphenicol, and tetracycline were discovered. o By 1953, a strain of Shigella was found that resisted these antibiotics and sulfanilamides. o By the 1970s, resistant strains of gonorrhea arose. The 1990s saw the development of true superbugs, bacteria that resist all known antibiotics. o One antibiotic of last resort is Vancomycin, a powerful antibiotic that attacks bacteria on many fronts. o Now there are Enterococci strains that resist Vancomycin. Multi-drug resistant tuberculosis strains have arisen. o By the 1940s and 1950s, a single antibiotic, such as Streptomycin, no longer cured tuberculosis, as it had in the past. o Tuberculosis is the leading cause of death by infectious disease in the world.


Below are listed some common antibiotics and their natural sources.
SOURCES OF ANTIBIOTICS Source molds penicillium cephalosporiu m actinomycetes penicillin cephalosporins tetracycline aminoglycosides (streptomycin) macrolides (erythromycin) chloramphenicol ivermectin rifamycins Dirt-dwelling organisms that form endospores and create antibiotics, possibly to deter bacterial competition. These organisms are unaffected by their own antibiotics, but can be susceptible to other antibiotics. Produce polypeptide antibiotics (e.g., polymyxin and bacitracin). Zwittermicin Linezolid (Zyvox)–Treat Gram-positive infections. Bind rRNA to prevent protein synthesis. Examples

bacteria bacilli

B. cereus synthetic oxazolidinones

MECHANISMS OF ANTIBIOTIC ACTION The many modes of antibiotic action are shown schematically in the diagram below.

Some specific examples

β -Lactam antibiotics
• • • • • •

Penicillin is a β-lactam antibiotic. These antibiotics contain a β-lactam ring—three carbons and one nitrogen. Transpeptidase crosslinks the peptidoglycan net in the cell wall of Gram-positive bacteria. The β-lactam ring mimics a component of the cell wall to which transpeptidase binds. Penicillin competitively inhibits the binding of transpeptidase. The affected bacterium will eventually lyse (rupture) because the unsupported cell wall cannot withstand its growth.

Disrupters of nucleic acid synthesis
• • • •

RNA polymerase synthesizes RNA according to a DNA template. The antibiotic rifampin interferes with prokaryotic RNA polymerase and thus, interferes with transcription. Fluoroquinolones inhibit DNA gyrase, a bacterial enzyme that unwinds DNA in preparation for replication and transcription. Both of these disruptions prevent bacteria from dividing to make more bacteria.

Disrupters of protein synthesis
• • • •

Aminoglycosides inhibit nucleic acid or protein synthesis in bacteria. They are L-shaped molecules that fit into L-shaped pockets of bacterial ribosomal RNA. When they insert themselves into rRNA, they disrupt ribosomal structure. Aminoglycosides don’t have this effect on human cells because the L-shaped pocket is specific to bacteria.

Inhibitors of metabolism
• •

Inhibit synthesis of purine and thymidylate precursors folic acid or tetrahydrofolate. Sulfonomides inhibit bacteria-specific reaction.

MECHANISM OF ACTION OF SELECTED ANTIBIOTICS Antibiotic Carbenicillin Pennicillin Mechanism Inhibits transpeptidation enzymes. Activates lytic enzymes of cell wall. Inhibits transpeptidase enzymes. Activates lytic enzymes of cell wall. The affected bacterium will eventually lyse because the unsupported cell wall cannot withstand its growth. Inhibits transpeptidation in cross-linking peptidoglycans. Interferes with bacterial cells at many levels, disrupting cell wall synthesis, interfering with RNA, and damaging the plasma membrane. Inhibits DNA gyrase; interferes with DNA replication. Blocks RNA synthesis by binding to and inhibiting RNA polymerase. Inhibitors of cell wall synthesis


Inhibitors of nucleic acid synthesis Ciprofloxacin Rifampin

Inhibitors of protein synthesis Chloramphenicol Blocks formation of new peptide bonds during protein synthesis by binding to the 50S subunit of the ribosome. Erthromycin Fusidic acid Linezolid Streptomycin Binds the 50S subunit and blocks translocation of the new protein on the ribosome, thus effectively halting synthesis. Blocks translocation. Binds rRNA to prevent translation initiation and thus protein synthesis. Binds the 30S ribosomal subunit of the tuberculosis bacterium and prevents the ribosome from forming the complex necessary to initiate protein translation. Streptomycin is the first line of chemical defense against Mycobacterium tuberculosis. Binds to the 30S subunit and blocks the addition of amino acids, producing incomplete and probably nonfunctional proteins. Interferes with synthesis of folic acid, which is required for the synthesis of purines and thymidine and for the synthesis of the amino acids methionine and gycine. Competitively inhibits dihydropteroate synthase, an enzyme that

Tetracyclines Metabolic inhibitors Dapsone


converts p-aminobenzoic acid (PABA) into folic acid. These drugs can also be incorporated into a compound that resembles dihydrofolate and that in turn can inhibit another enzyme in the pathway, dihydrofate reductase. Trimethoprim Inhibits dihydrofolate reductase, blocking tetrahydrofolate synthesis.

MECHANISMS OF RESISTANCE Bacteria either have preexisting resistance to drugs, or they develop resistance. Human activity has contributed greatly to the increase in resistant strains of bacteria. Often, when bacteria acquire resistance to a certain drug from a particular class (e.g., the penicillins), the bacteria also acquire resistance to all other drugs in that class. Some of the many mechanisms of resistance are indicated schematically in the following diagram:

Inherent resistance The principles of Darwinian evolution act on bacteria with inherent resistance: those bacteria that resist an antibiotic's effects are better suited to survive in an environment that contains the antibiotic. In the case of inherent resistance and vertical evolution, the genes that confer resistance are found on bacterial chromosomes and are transferred to the bacterial progeny every time the cell divides.

Bacteria may begin life resistant to a particular antibiotic. o Example: Gram-negative bacteria are naturally resistant to penicillins. Bacteria may be resistant because either

they have no mechanism to transport the drug into the cell. o they do not contain or rely on the antibiotic’s target process or protein. Specific examples of bacterial strains with known natural resistance: o tetracycline-resistant Proteus mirabilis. o ampicillin-resistant Klebsiella pneumoniae.

Acquired resistance Bacteria that don’t begin life resistant to a certain antibiotic can acquire that resistance. In the case of vertical evolution and inherent resistance, mutations occur on chromosomes and are then selected for an environment where resistance increases fitness. In the case of horizontal evolution, genes pass from a resistant strain to a nonresistant strain, conferring resistance on the latter. The introduction of an antibiotic alters the environment and acts as a selective pressure. Conjugation Transmission of resistance genes via plasmid exchange.
• • •

Bacteria have circles of DNA called plasmids that they can pass to other bacteria during conjugation. Plasmids, the key players in conjugation, are even referred to as resistance transfer factors. This type of acquisition allows resistance to spread among a population of bacterial cells much faster than simple mutation and vertical evolution would permit.

Transduction A virus serves as the agent of transfer between bacterial strains. Transformation DNA released from a bacterium is picked up by a new cell. After the new DNA is introduced—whether via conjugation, transduction, or transformation—it is incorporated into the cell and results in the emergence of a new, resistant genotype.

SOME EXAMPLES OF RESISTANCE Type of bacteria Gram-negative bacteria Proteus mirabilis (rheumatoid arthritis, urinary tract infections) Klebsiella pneumoniae (ankylosing spondylitis, a disease of the joints) Staphylococcus aureus Resistance to Penicillin and other β-lactam antibiotics Tetracycline Ampicillin Methicillin

Some mechanisms of resistance Enzyme-based resistance There are a number of ways enzymes have been used by bacteria to confer antibiotic resistance:
• •

Resist β-lactam antibiotics through modifications in the genetic code for the proteins that bind penicillin. Genes for enzymes that can destroy or disable antibiotics are acquired or arise through mutation. For example, a β-lactamase enzyme can destroy the β-lactam ring of penicillins through hydrolysis, and without a β-lactam ring, penicillins are ineffective against the bacteria.

Prevent aminoglycoside disruption of ribosomes. A bacterial enzyme adds a bulky substituent to the aminoglycoside, making it impossible for the drug to fit into the rRNA pocket and rendering it harmless.

Ribosomal modifications The ribosome can be methylated so that an antibiotic cannot bind to it. Protein modifications

For antibiotics that target DNA gyrase, the enzyme that unwinds DNA for replication, random mutations in the bacterial DNA may alter the gyrase and make it unrecognizable to antibiotics while still leaving it functional. Metabolic resistance In the case of sulfonamides, which operate by mimicking PABA and competing for an enzyme that synthesizes folic acid, an increase in the amount of PABA can outcompete the sulfonamide and render it ineffective; or an alteration in the code for the enzyme itself can prevent its sulfonamide binding.

Effluxing the toxin One particularly active way a bacterium may deal with an antibiotic is to pump it out, perhaps using proteins encoded by acquired genes. For example, a strain of enterococcal bacteria can pump out tetracycline. This type of pumping is called an “efflux phenomenon.” Note: Bacteria without inherent antibiotic resistance can acquire—through conjugation, transduction, or transformation—the genes that encode proteins that confer resistance. WHAT THE FUTURE HOLDS We use antibiotics for everything from treating viral infections—against which antibiotics are useless—to promoting the growth of livestock to curing acne. People often demand antibiotics from their doctors even in the absence of proof of a bacterial infection. And people often neglect to complete a full course of antibiotics once it has been prescribed.

The more often we use antibiotics, the more likely it is that resistance will develop and spread. Today, about 30% of Streptococcus pneumoniae strains are resistant to penicillin, and 30% of gonorrhea bacteria are resistant to penicillin or tetracycline or both. Salmonella typhimurium is resistant to ampicillin, sulfa drugs, streptomycin, tetracycline, and chloramphenicol. Even the antibiotic of last resort, vancomycin, has become ineffectual against some superstrains. Researchers are turning now to synthetic antibiotics for help against these superbugs. The good news may be that resistance can disappear in the same way it developed. Mutations that reduce resistance may occur, and if the antibiotic is not present, there is no selective pressure to maintain resistance. In the absence of selective pressure, the bacteria may eventually lose all of their resistance.

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