Treatment of Infectious Diseases
While literally meaning "destroyer of life," the term "antibiotic" has become the most commonly used word to refer to a chemical substance used to treat bacterial infections. The term "antimicrobial" has a somewhat broader connotation, generally referring to anything that inhibits the growth of microbes. Technically, the term antimicrobial does not encompass the "antihelminthic" drugs because worms are not microscopically small. Antimicrobials can be either microbistatic (inhibiting the replication of the microbe) or microbicidal (actually killing the target microorganism). In the former case, a combination of therapy and immunity may be required to finally terminate the infection.
Treatment of bacterial diseases.
Because bacteria are prokaryotes, it has been relatively easy to find and develop antibacterial drugs that have minimal side effects. These drugs target structural features and metabolic characteristics of prokaryotes that are significantly different from those in eukaryotic cells. Drugs used to treat bacterial diseases can be grouped into categories based on their modes of action. In general, these drugs inhibit cell wall synthesis, protein synthesis, nucleic acid synthesis, or other enzyme-catalyzed reactions.
The penicillins and cephalosporins all interfere with the synthesis of the peptidoglycan layer in prokaryotic cell walls. Because eukaryotes have neither the peptidoglycan components nor the enzymes that synthesize them, these drugs do not affect the host cells. A second class of drugs, including chloramphenicol, the tetracyclines, and erythromycin, bind to prokaryotic ribosomes and inhibit protein synthesis. Prokaryotic ribosomes are structurally different from eukaryotic ribosomes, so these drugs have minimal effect on eukaryotic cells. Nevertheless, some of them may be toxic to some human tissues when they are used in high doses or for prolonged periods of time.
Rifampicin is one of the antibiotics frequently used for treating tuberculosis. This drug inhibits prokaryotic RNA synthesis. DNA synthesis in prokaryotes may be inhibited by the fluoroquinolones. In contrast, the sulfonamides stop bacterial infections by inhibiting other enzymes. Sulfonamides interfere with the synthesis of folic acid, a vitamin necessary for nucleic acid synthesis. Most bacteria must synthesize their own folic acid because their membranes are impermeable to external folic acid. Mammalian cells are not affected by sulfonamides because they are unable to make their own folic acid and have evolved mechanisms for transporting external folic acid across their membranes.
Treatment of Viral Diseases.
In general, drugs that effectively inhibit viral infections are highly toxic to host cells because viruses use the host's metabolic enzymes in their reproduction. For this reason, most illnesses due to viruses are treated symptomatically until the host's immune system controls and eliminates the pathogen (or the host dies). Antiviral drugs that are used typically target virus-specific enzymes involved in viral nucleic acid synthesis. One of the most familiar of these drugs is acyclovir, which is used to treat outbreaks of genital herpes. Amantadine is an antiviral drug sometimes used to prevent or moderate influenza among those at high risk of severe illness from the disease. In addition to antiviral drugs that inhibit the replication of the HIV genome (such as AZT), AIDS patients today are also prescribed proteases that interfere with the packaging of the HIV genome into virus particles.
Treatment of Fungal & Parasitic Diseases.
The development of drugs to treat fungal, protozoan, and helminthic diseases is challenging because agents that kill or inhibit the growth of these eukaryotic organisms are also highly toxic to mammalian cells. Because fungi and protozoa are rapidly proliferating cells, drugs against these organisms tend to target key components of their replicative or biosynthetic pathways. Common antifungals inhibit sterol syntheses (the azole derivatives) or disrupt the cell membrane (polyenes like amphotericin B). Most antihelminthic drugs target adult worms, which are no longer growing and do not replicate. These drugs are often aimed at inhibiting fundamental processes, such as energy production and muscle function (for example, the benzimidazoles and avermectins), or at targets involved in egg production or larval development.
Malaria, a protozoan disease, was successfully treated for many years with chloroquine. In recent decades, Plasmodium species that are resistant to this drug have appeared and spread to areas where malaria is a common threat. In those areas, a combination of the drugs sulfonamide and pyrimethamine is frequently used to treat the disease.
Resistance To Antimicrobial Agents.
One of the ongoing problems scientists and medical workers face in the fight against infectious diseases is the development of resistance to the agents used to control them. The phenomenon of resistance has been known since almost the beginning of antibiotic use. For example, penicillin was introduced for clinical use in treating bacterial infections in the 1940s. As early as 1943, Alexander Fleming, the discoverer of penicillin, observed that some bacteria were resistant to the drug and warned that indiscriminate use of penicillin would lead to the proliferation of resistant pathogenic bacteria. By 1946, medical staff at a London hospital estimated that 14 percent of the staphylococcal strains isolated from their patients were resistant to penicillin. Today, more than 90 percent of these bacteria are resistant. In an environment of widespread penicillin use, selection for resistant bacteria occurred; that is, the pathogenic organisms evolved.
The same process has occurred for many other antimicrobial drugs. Alarmingly, many pathogens are simultaneously acquiring resistance to multiple drugs. For example, some strains of Mycobacterium tuberculosis are resistant to all of the currently available drugs used for treatment.
Mechanisms of Antimicrobial Resistance.
Antibiotic resistance appears as a result of changes in genes or the acquisition of genes that allow the pathogen to evade the action of antimicrobial drugs. Resistance mechanisms include structural changes in or around the target molecule that inhibit the drugs' ability to bind to it; reduced permeability of the cell membrane to the drug, actively pumping the drug out of the cell after it has entered; and production of enzymes that inactivate the antibiotic after it has been taken up by the cell. Microbes that produce larger than normal amounts of the target molecule may be "less susceptible" (as opposed to resistant) to a drug, meaning it takes a higher drug level to adversely affect that microbe.
Transfer of Antimicrobial-Resistance Genes.
Bacteria have many methods for developing resistance. Antibiotic resistance initially arises as mutations to existing genes; however, many (probably most) bacteria acquire these genes rather than experience the mutation themselves. Resistance genes are transferred to other members of the same species and across species by a variety of bacterial genetic exchange mechanisms. Many gram-negative bacteria, including Escherichia coli and Salmonella species, can transfer extra-chromosomal genetic material called plasmids via the process of conjugation.
Bacteria endowed with the plasmids have numerous pili along their surfaces; one of these extends to a plasmid-lacking bacterium as a conjugation tube. The plasmid then replicates, and one copy travels through the conjugation tube into the recipient bacterium. One large class of plasmids is called resistance plasmids because they carry genes that confer antibiotic resistance. Many resistance plasmids carry genes for resistance to multiple antibiotics; thus, one conjugation event can simultaneously transfer resistance to several antibiotics.
Some species of bacteria are capable of taking up free-floating bits of DNA from their environments in a process known as bacterial transformation. If they take up a DNA fragment containing an antibiotic resistance gene, they may become resistant to that antibiotic. Another mechanism of genetic exchange in bacteria is transduction. Bacteria are subject to viral infection. When a bacteria cell is infected, the virus takes over the cell's metabolism, directing synthesis of its genetic material and production of the components of the viral particle. Simultaneously, the host bacterial DNA is degraded. In the last stage of virus production, its genetic material is encapsulated in a protein coat. Occasionally, a piece of the host bacterial DNA may be packaged in a viral particle. The resulting "transducing particle," like a normal viral particle, has the ability to attach to a recipient bacterium and transfer its genetic material into the cell. However, in this case, the transferred genetic material may be a bacterial gene that pro vides resistance to an antibiotic.
Finally, many transposons carry antibioticresistance genes. Transposons are sequences of DNA that are capable of inserting themselves randomly into genomes. Because they do not appear to rely on specific genetic sequences of the target insertion site, they can readily move across species.
Although mutations that result in antibiotic resistance and, less so, bacterial genetic exchange, are rare events, they need occur only once. In an environment of heavy antibiotic use, the forces of natural selection will favor the propagation of resistant variants of a pathogen. The human body is a rich environment for the growth of large numbers of bacteria and for the interaction of a variety of pathogenic and nonpathogenic bacteria. Thus, there is optimal opportunity for rare mutational and genetic exchange events.
Other pathogens have more limited options for drug resistance. Strains of pathogens develop that are naturally less susceptible to a particular drug due to a normally occurring mutation. In the face of continuing drug use, this strain rapidly grows out of the population being spread through the usual transmission process. Malaria, a protozoan disease, was successfully treated for many years with chloroquine, a drug that was widely available over the counter in regions where malaria was a problem. In recent decades, Plasmodium strains that are resistant to this drug have appeared and spread throughout Africa, South America, and Southeast Asia.
Pathogens that cause infectious diseases
References:
1. 1. NIH Curriculum Supplement Series, Understanding Emerging and Re-emerging Infectious Diseases
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