Although it may be administered orally or intramuscularly in some circumstances, bacitracin has been shown to be nephrotoxic damaging to the kidneys.
Therefore, it is more commonly combined with neomycin and polymyxin in topical ointments such as Neosporin. The cytoplasmic ribosomes found in animal cells 80S are structurally distinct from those found in bacterial cells 70S , making protein biosynthesis a good selective target for antibacterial drugs.
Several types of protein biosynthesis inhibitors are discussed in this section and are summarized in Figure 3. Figure 3. The major classes of protein synthesis inhibitors target the 30S or 50S subunits of cytoplasmic ribosomes. Aminoglycosides are large, highly polar antibacterial drugs that bind to the 30S subunit of bacterial ribosomes, impairing the proofreading ability of the ribosomal complex. This impairment causes mismatches between codons and anticodons, resulting in the production of proteins with incorrect amino acids and shortened proteins that insert into the cytoplasmic membrane.
Disruption of the cytoplasmic membrane by the faulty proteins kills the bacterial cells. The aminoglycosides , which include drugs such as streptomycin , gentamicin , neomycin , and kanamycin , are potent broad-spectrum antibacterials. However, aminoglycosides have been shown to be nephrotoxic damaging to kidney , neurotoxic damaging to the nervous system , and ototoxic damaging to the ear.
Another class of antibacterial compounds that bind to the 30S subunit is the tetracyclines. In contrast to aminoglycosides, these drugs are bacteriostatic and inhibit protein synthesis by blocking the association of tRNAs with the ribosome during translation.
Naturally occurring tetracyclines produced by various strains of Streptomyces were first discovered in the s, and several semisynthetic tetracyclines, including doxycycline and tigecycline have also been produced. Although the tetracyclines are broad spectrum in their coverage of bacterial pathogens, side effects that can limit their use include phototoxicity , permanent discoloration of developing teeth, and liver toxicity with high doses or in patients with kidney impairment.
There are several classes of antibacterial drugs that work through binding to the 50S subunit of bacterial ribosomes. The macrolide antibacterial drugs have a large, complex ring structure and are part of a larger class of naturally produced secondary metabolites called polyketides , complex compounds produced in a stepwise fashion through the repeated addition of two-carbon units by a mechanism similar to that used for fatty acid synthesis.
Macrolides are broad-spectrum, bacteriostatic drugs that block elongation of proteins by inhibiting peptide bond formation between specific combinations of amino acids. The first macrolide was erythromycin.
It was isolated in from Streptomyces erythreus and prevents translocation. Semisynthetic macrolides include azithromycin and telithromycin. Compared with erythromycin, azithromycin has a broader spectrum of activity, fewer side effects, and a significantly longer half-life 1. Telithromycin is the first semisynthetic within the class known as ketolides. The lincosamides include the naturally produced lincomycin and semisynthetic clindamycin.
Although structurally distinct from macrolides, lincosamides are similar in their mode of action to the macrolides through binding to the 50S ribosomal subunit and preventing peptide bond formation. Lincosamides are particularly active against streptococcal and staphylococcal infections. The drug chloramphenicol represents yet another structurally distinct class of antibacterials that also bind to the 50S ribosome, inhibiting peptide bond formation.
Chloramphenicol, produced by Streptomyces venezuelae , was discovered in ; in , it became the first broad-spectrum antibiotic that was approved by the FDA. Although it is a natural antibiotic, it is also easily synthesized and was the first antibacterial drug synthetically mass produced.
As a result of its mass production, broad-spectrum coverage, and ability to penetrate into tissues efficiently, chloramphenicol was historically used to treat a wide range of infections, from meningitis to typhoid fever to conjunctivitis. Unfortunately, serious side effects, such as lethal gray baby syndrome , and suppression of bone marrow production, have limited its clinical role.
Chloramphenicol also causes anemia in two different ways. One mechanism involves the targeting of mitochondrial ribosomes within hematopoietic stem cells, causing a reversible, dose-dependent suppression of blood cell production. Once chloramphenicol dosing is discontinued, blood cell production returns to normal. This mechanism highlights the similarity between 70S ribosomes of bacteria and the 70S ribosomes within our mitochondria.
The second mechanism of anemia is idiosyncratic i. This mechanism of aplastic anemia is not dose dependent and can develop after therapy has stopped. Because of toxicity concerns, chloramphenicol usage in humans is now rare in the United States and is limited to severe infections unable to be treated by less toxic antibiotics.
Because its side effects are much less severe in animals, it is used in veterinary medicine. The oxazolidinones , including linezolid , are a new broad-spectrum class of synthetic protein synthesis inhibitors that bind to the 50S ribosomal subunit of both gram-positive and gram-negative bacteria. However, their mechanism of action seems somewhat different from that of the other 50S subunit-binding protein synthesis inhibitors already discussed. Instead, they seem to interfere with formation of the initiation complex association of the 50S subunit, 30S subunit, and other factors for translation, and they prevent translocation of the growing protein from the ribosomal A site to the P site.
Table 3 summarizes the protein synthesis inhibitors. A small group of antibacterials target the bacterial membrane as their mode of action Table 4. The polymyxins are natural polypeptide antibiotics that were first discovered in as products of Bacillus polymyxa ; only polymyxin B and polymyxin E colistin have been used clinically.
They are lipophilic with detergent-like properties and interact with the lipopolysaccharide component of the outer membrane of gram-negative bacteria, ultimately disrupting both their outer and inner membranes and killing the bacterial cells. Unfortunately, the membrane-targeting mechanism is not a selective toxicity , and these drugs also target and damage the membrane of cells in the kidney and nervous system when administered systemically.
Because of these serious side effects and their poor absorption from the digestive tract, polymyxin B is used in over-the-counter topical antibiotic ointments e.
However, the emergence and spread of multidrug-resistant pathogens has led to increased use of intravenous colistin in hospitals, often as a drug of last resort to treat serious infections. The antibacterial daptomycin is a cyclic lipopeptide produced by Streptomyces roseosporus that seems to work like the polymyxins, inserting in the bacterial cell membrane and disrupting it.
However, in contrast to polymyxin B and colistin, which target only gram-negative bacteria, daptomycin specifically targets gram-positive bacteria. It is typically administered intravenously and seems to be well tolerated, showing reversible toxicity in skeletal muscles.
Some antibacterial drugs work by inhibiting nucleic acid synthesis Table 5. For example, metronidazole is a semisynthetic member of the nitroimidazole family that is also an antiprotozoan. It interferes with DNA replication in target cells. The drug rifampin is a semisynthetic member of the rifamycin family and functions by blocking RNA polymerase activity in bacteria.
The RNA polymerase enzymes in bacteria are structurally different from those in eukaryotes, providing for selective toxicity against bacterial cells. It is used for the treatment of a variety of infections, but its primary use, often in a cocktail with other antibacterial drugs, is against mycobacteria that cause tuberculosis. Nearly every bacterium has a peptidoglycan cell wall. The composition of the cell wall differs depending on the type of organism, so penicillin does not affect other organisms.
The cell walls of plants, for example, are made from cellulose. The cell walls of algae are highly variable. Algae cell walls can be made of cellulose, xylan, silica, carrageenan or a variety of other materials. The cell walls of most fungi are made from chitin. Composition of the cell wall in the archaea is more diverse. Within bacteria, there are two types of bacterial cell walls. Gram-positive bacteria have a peptidoglycan layer on the outside of the cell wall.
Gram-negative bacteria have peptidoglycan between membranes. Penicillin works best on gram-positive bacteria by inhibiting peptidoglycan production, making the cells leaky and fragile. The cells burst open and are much easier for the immune system to break down, which helps the sick person heal more quickly.
Human cells do not contain peptidoglycan, so penicillin specifically targets bacterial cells. Other antibiotics target different molecules that inhibit bacterial growth while leaving human cells undamaged. Sulfa antibiotics target a specific enzyme that inhibits bacterial growth. Scientists have discovered a protein that prevents bacteria from exploding, which could make it a good target for future antibiotics. But in people with weak immune systems, the bacteria can cause disease.
Although penicillin was discovered nearly a century ago, scientists are still learning how the drug makes bacterial cells pop like overfilled balloons. Now, in a study of the disease-causing bacterium Streptococcus pneumoniae, researchers have discovered a suite of molecules involved in penicillin-induced bursting. He and his colleagues report the work April 9, , in the journal eLife. They hope their finding will help scientists develop new antibiotics to kill bacteria that have become insensitive to current drugs.
Penicillin is part of a class of drugs called beta-lactams, which are the most widely used antibiotics in the world. In , for example, the Centers for Disease Control and Prevention reported that about 30 percent of S. Escherichia coli cells burst after treatment with ampicillin, a derivative of penicillin. Scientists believe that these cells burst due to the action of enzymes that break down the cell wall.
Credit: Bernhardt Lab. One way to design new antibiotics is to learn more about the molecular chain of events initiated by current ones. Since , when Alexander Fleming accidentally discovered penicillin, scientists have learned that beta-lactams cause bacteria to explode under the force of incoming water.
The bacteria targeted by these drugs are surrounded by two barriers to the outside world: an oily inner membrane and a stiffer outer cell wall.
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