Antimicrobial Agents in the Treatment of Infectious Disease
(page 1)
Introduction
Most microbiologists distinguish two groups of antimicrobial agents used in the treatment of infectious disease: antibiotics, which are natural substances produced by certain groups of microorganisms, and chemotherapeutic agents, which are chemically synthesized. A hybrid substance is a semisynthetic antibiotic, wherein a molecular version produced by the microbe is subsequently modified by the chemist to achieve desired properties. Furthermore, some antimicrobial compounds, originally discovered as products of microorganisms, can be synthesized entirely by chemical means. In the medical and parmaceutical worlds, all these antimicrobial agents used in the treatment of disease are referred to as antibiotics, interpreting the word literally.
The modern era of antimicrobial chemotherapy began in 1929, with Fleming's discovery of the powerful bactericidal substance, penicillin, and Domagk's discovery in 1935 of synthetic chemicals (sulfonamides) with broad antimicrobial activity.
In the early 1940's, spurred partially by the need for antibacterial agents in WW II, penicillin was isolated and purified and injected into experimental animals, where it was found not only to cure infections but also to possess incredibly low toxicity for the animals. This fact ushered into being the age of antibiotic chemotherapy, and an intense search for similar antimicrobial agents of low toxicity to animals that might prove useful in the treatment of infectious disease. The rapid isolation of streptomycin, chloramphenicol and tetracycline soon followed, and by the 1950's, these and several other antibiotics were in clinical usage.
Microorganisms that Produce Antibiotics
The bacterial colonies at 10 o'clock, 2 o'clock and 8 o'clock on this agar plate are producing antibiotics that inhibit encroachment by the mold which is growing out from the center.
Most of the natural antibiotics that are being used in agriculture and medicine are produced by three unrelated groups of microbes, including eucaryotic molds and two types of spore-forming bacteria. However, many culturable, and some non culturable microbes, have been shown to produce various substances that inhibit other organisms that grow in their space. If we consider antibiotics as secondary metabolites of microbes, it narrows the field to the handful of microbes discussed below.
1. Penicillium and Cephalosporium molds produce beta-lactam antibiotics such as penicillin and cephalosporin and their relatives. They also produce the base molecule for development of semisynthetic beta-lactam antibiotics, such as amoxacillin and ampicillin. Beta-lactams are used to treat about one-third of outpatients with bacterial infections.
The natural habitat of molds is soil. And although sex is sometimes involved, they reproduce by spore formation. They are foremost in their abilities to degrade organic matter, and they play their most important role in natures in biodegradation and the carbon cycle. Most of us know that molds will grow on nearly anything that is organic and moist, so they are also responsible for a lot food spoilage as well as decomposition of our structural materials and textiles. "Nothing is forever", with molds around.
Three colonies of a Penicillium mold growing on an agar medium. The green fuzzy appearance is the asexual spores of the fungus.
2. Actinomycetes, mainly Streptomyces species, produce tetracyclines, aminoglycosides (streptomycin and its relatives), macrolides (erythromycin and its relatives), chloramphenicol, ivermectin, rifamycins, and most other clinically-useful antibiotics that are not beta-lactams. Actinomycetes are the mainstay of the antibiotics industry.
Actinomycetes are a group of branched bacteria that reproduce by spore formation. They come from a phylum of Bacteria, Actinobacteria, and they are landed in Order Actinomycetales. Some of the representative family include such diverse bacteria as Actinomyces, Corynebacterium, Nocardia, Propionibacter, Streptomyces, Micromonospora and Frankia. Most actinomycetes are inhabitants of the soil. The characteristic odor of damp soil is due to the production of substances, called geosmins, by these bacteria
Two different actinomycetes were spotted in the center of the agar plate about two centimeters apart. This peculiar pattern of growth was observed after a 10-day incubation period. What could be going on? Courtesy of Jerry Ensign Department of Bacteriology. "Chance favors the prepared mind."
3. Bacillus species, such as B. polymyxa and B. subtilis, produce polypeptide antibiotics (e.g. polymyxin and bacitracin), and B. cereus produces zwittermicin. Bacillus species have the relatively rare ability to form a type of resting cell called an endospore. Bacilli are Gram-positive, rod-shaped, aerobic bacteria that live in the soil. They play an important ecological role in aerobic decomposition, biodegradation and mineral recycling.
A swirl of Bacillus mycoides colonies growth amidst other bacteria and molds from the soil. The swirls are always counterclockwise, at least in the Northern Hemisphere where I have seen it.
These organisms all have in common that they live in soil and they form some sort of a spore or resting structure. It is not known why these microorganisms produce antibiotics, but the answer may be in the obvious - it affords them some nutritional or spatial advantage in their habitat by antagonizing the competition; or it may be in the subtle - it acts as some sort of hormone or signal molecule associated with sporulation or dormancy or germination. Antibiotics are secondary metabolites and they are produced at the same time that the cells begin their sporulation processes.
Antibiotics tend to be rather large, complicated organic molecules and may require as many as 30 separate enzymatic steps to synthesize. The maintenance of a substantial component of the bacterial genome devoted solely to the synthesis of an antibiotic leads one to conclude that the antibiotic is important, if not essential, to the survival of these organisms in their natural habitat.
Most of the microorganisms that produce antibiotics are resistant to the action of their own antibiotic, although the organisms are affected by other antibiotics, and their antibiotic may be effective against closely-related strains. In most cases, how or why bacteria are resistant to their own antibiotics is also unknown, but it may be worth pondering or studying if we are to understand the cellular and molecular basis of drug resistance in pathogens.
Antibiotics must have Selective Toxicity for the Microbe
Several hundreds of compounds with antibiotic activity have been isolated from microorganisms over the years, but only a few of them are clinically-useful. The reason for this is that only compounds with selective toxicity can be used clinically.
The selective toxicity of antibiotics means that they must be highly effective against the microbe but have minimal or no toxicity to humans. In practice, this is expressed by a drug's therapeutic index (TI) - the ratio of the toxic dose (to the patient) to the therapeutic dose (to eliminate the infection). The larger the index, the safer is the drug (antibiotic) for human use.
The selective toxicity of antibiotics is brought about by finding vulnerable targets for the drug in the microbe that do not exist in the animal (eucaryote) that is given the drug. Most antibiotics in clinical usage are directed against bacterial cell wall synthesis, bacterial protein synthesis, or bacterial nucleic acid synthesis, which are unique in some ways to bacteria. For example, the beta lactam antibiotics (penicillin and its relatives) inhibit peptidoglycan synthesis in the cell wall. Humans have neither a cell wall nor peptidoglycan and so are unaffected by the action of the drug. Other antibiotics, including streptomycin and the tetracyclines, target bacterial protein synthesis because bacterial ribosomes (termed 70S ribosomes) are different from the ribosomes (80S) of humans and other eucaryotic organisms. Antibiotics such as the flouroqinolones (e.g. ciprofloxacin) inhibit procaryotic (not eucaryotic) DNA replication, and rifamycins inhibit bacterial (not eucaryotic) DNA transcription.
Kinds of Antimicrobial Agents and their Primary Modes of Action
Protein synthesis inhibitors
The tetracycline core structure. The tetracyclines are a large family of antibiotics that were discovered as natural products of Streptomyces bacteria beginning in the late 1940s. Tetracycline sparked the development of many chemically altered antibiotics and in doing so has proved to be one of the most important discoveries made in the field of antibiotics. It is a classic "broad-spectrum antibiotic" used to treat infections caused by Gram-positive and Gram-negative bacteria and some protozoa.
Doxycycline is a semisynthetic tetracycline developed in the 1960s. It is frequently used to treat chronic prostatitis, sinusitis, syphilis, chlamydia, pelvic inflammatory disease, acne and rosacea. In addition, it is used in the treatment and prophylaxis of anthrax and in prophylaxis against malaria. It is also effective against Yersinia pestis (the infectious agent of bubonic plague) and is prescribed for the treatment of Lyme disease, ehrlichiosis and Rocky Mountain spotted fever. Because doxycycline is one of the few medications that is effective in treating Rocky Mountain spotted fever (with the next best alternative being chloramphenicol), it is indicated even for use in children for this illness.
Chemical structure of chloramphenicol
Chemical structure of a macrolide antibiotic, erythromycin.
Azithromycin, shown above, is a subclass of macrolide antibiotics. Azithromycin is one of the world's best-selling antibiotics. It is s derived from erythromycin, but it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring, thus making the lactone ring 15-membered. Azithromycin is used to treat certain bacterial infections, most often bacteria causing middle ear infections, tonsillitis, throat infections, laryngitis, bronchitis, pneumonia and sinusitis. It is also effective against certain sexually transmitted diseases, such as non-gonococcal urethritis and cervicitis.
Clindamycin is a lincosamide antibiotic. It is usually used to treat infections with anaerobic bacteria but can also be used to treat some protozoal diseases, such as malaria. It is a common topical treatment for acne, and can be useful against some methicillin-resistant Staphylococcus aureus (MRSA) infections. The most severe common adverse effect of clindamycin is Clostridium difficile-associated diarrhea (the most frequent cause of pseudomembranous colitis). Although this side-effect occurs with almost all antibiotics, including beta-lactam antibiotics, it is classically linked to clindamycin use.
END OF CHAPTER
(page 1)
Introduction
Most microbiologists distinguish two groups of antimicrobial agents used in the treatment of infectious disease: antibiotics, which are natural substances produced by certain groups of microorganisms, and chemotherapeutic agents, which are chemically synthesized. A hybrid substance is a semisynthetic antibiotic, wherein a molecular version produced by the microbe is subsequently modified by the chemist to achieve desired properties. Furthermore, some antimicrobial compounds, originally discovered as products of microorganisms, can be synthesized entirely by chemical means. In the medical and parmaceutical worlds, all these antimicrobial agents used in the treatment of disease are referred to as antibiotics, interpreting the word literally.
The modern era of antimicrobial chemotherapy began in 1929, with Fleming's discovery of the powerful bactericidal substance, penicillin, and Domagk's discovery in 1935 of synthetic chemicals (sulfonamides) with broad antimicrobial activity.
In the early 1940's, spurred partially by the need for antibacterial agents in WW II, penicillin was isolated and purified and injected into experimental animals, where it was found not only to cure infections but also to possess incredibly low toxicity for the animals. This fact ushered into being the age of antibiotic chemotherapy, and an intense search for similar antimicrobial agents of low toxicity to animals that might prove useful in the treatment of infectious disease. The rapid isolation of streptomycin, chloramphenicol and tetracycline soon followed, and by the 1950's, these and several other antibiotics were in clinical usage.
Microorganisms that Produce Antibiotics
The bacterial colonies at 10 o'clock, 2 o'clock and 8 o'clock on this agar plate are producing antibiotics that inhibit encroachment by the mold which is growing out from the center.
Most of the natural antibiotics that are being used in agriculture and medicine are produced by three unrelated groups of microbes, including eucaryotic molds and two types of spore-forming bacteria. However, many culturable, and some non culturable microbes, have been shown to produce various substances that inhibit other organisms that grow in their space. If we consider antibiotics as secondary metabolites of microbes, it narrows the field to the handful of microbes discussed below.
1. Penicillium and Cephalosporium molds produce beta-lactam antibiotics such as penicillin and cephalosporin and their relatives. They also produce the base molecule for development of semisynthetic beta-lactam antibiotics, such as amoxacillin and ampicillin. Beta-lactams are used to treat about one-third of outpatients with bacterial infections.
The natural habitat of molds is soil. And although sex is sometimes involved, they reproduce by spore formation. They are foremost in their abilities to degrade organic matter, and they play their most important role in natures in biodegradation and the carbon cycle. Most of us know that molds will grow on nearly anything that is organic and moist, so they are also responsible for a lot food spoilage as well as decomposition of our structural materials and textiles. "Nothing is forever", with molds around.
Three colonies of a Penicillium mold growing on an agar medium. The green fuzzy appearance is the asexual spores of the fungus.
2. Actinomycetes, mainly Streptomyces species, produce tetracyclines, aminoglycosides (streptomycin and its relatives), macrolides (erythromycin and its relatives), chloramphenicol, ivermectin, rifamycins, and most other clinically-useful antibiotics that are not beta-lactams. Actinomycetes are the mainstay of the antibiotics industry.
Actinomycetes are a group of branched bacteria that reproduce by spore formation. They come from a phylum of Bacteria, Actinobacteria, and they are landed in Order Actinomycetales. Some of the representative family include such diverse bacteria as Actinomyces, Corynebacterium, Nocardia, Propionibacter, Streptomyces, Micromonospora and Frankia. Most actinomycetes are inhabitants of the soil. The characteristic odor of damp soil is due to the production of substances, called geosmins, by these bacteria
Two different actinomycetes were spotted in the center of the agar plate about two centimeters apart. This peculiar pattern of growth was observed after a 10-day incubation period. What could be going on? Courtesy of Jerry Ensign Department of Bacteriology. "Chance favors the prepared mind."
3. Bacillus species, such as B. polymyxa and B. subtilis, produce polypeptide antibiotics (e.g. polymyxin and bacitracin), and B. cereus produces zwittermicin. Bacillus species have the relatively rare ability to form a type of resting cell called an endospore. Bacilli are Gram-positive, rod-shaped, aerobic bacteria that live in the soil. They play an important ecological role in aerobic decomposition, biodegradation and mineral recycling.
A swirl of Bacillus mycoides colonies growth amidst other bacteria and molds from the soil. The swirls are always counterclockwise, at least in the Northern Hemisphere where I have seen it.
These organisms all have in common that they live in soil and they form some sort of a spore or resting structure. It is not known why these microorganisms produce antibiotics, but the answer may be in the obvious - it affords them some nutritional or spatial advantage in their habitat by antagonizing the competition; or it may be in the subtle - it acts as some sort of hormone or signal molecule associated with sporulation or dormancy or germination. Antibiotics are secondary metabolites and they are produced at the same time that the cells begin their sporulation processes.
Antibiotics tend to be rather large, complicated organic molecules and may require as many as 30 separate enzymatic steps to synthesize. The maintenance of a substantial component of the bacterial genome devoted solely to the synthesis of an antibiotic leads one to conclude that the antibiotic is important, if not essential, to the survival of these organisms in their natural habitat.
Most of the microorganisms that produce antibiotics are resistant to the action of their own antibiotic, although the organisms are affected by other antibiotics, and their antibiotic may be effective against closely-related strains. In most cases, how or why bacteria are resistant to their own antibiotics is also unknown, but it may be worth pondering or studying if we are to understand the cellular and molecular basis of drug resistance in pathogens.
Antibiotics must have Selective Toxicity for the Microbe
Several hundreds of compounds with antibiotic activity have been isolated from microorganisms over the years, but only a few of them are clinically-useful. The reason for this is that only compounds with selective toxicity can be used clinically.
The selective toxicity of antibiotics means that they must be highly effective against the microbe but have minimal or no toxicity to humans. In practice, this is expressed by a drug's therapeutic index (TI) - the ratio of the toxic dose (to the patient) to the therapeutic dose (to eliminate the infection). The larger the index, the safer is the drug (antibiotic) for human use.
The selective toxicity of antibiotics is brought about by finding vulnerable targets for the drug in the microbe that do not exist in the animal (eucaryote) that is given the drug. Most antibiotics in clinical usage are directed against bacterial cell wall synthesis, bacterial protein synthesis, or bacterial nucleic acid synthesis, which are unique in some ways to bacteria. For example, the beta lactam antibiotics (penicillin and its relatives) inhibit peptidoglycan synthesis in the cell wall. Humans have neither a cell wall nor peptidoglycan and so are unaffected by the action of the drug. Other antibiotics, including streptomycin and the tetracyclines, target bacterial protein synthesis because bacterial ribosomes (termed 70S ribosomes) are different from the ribosomes (80S) of humans and other eucaryotic organisms. Antibiotics such as the flouroqinolones (e.g. ciprofloxacin) inhibit procaryotic (not eucaryotic) DNA replication, and rifamycins inhibit bacterial (not eucaryotic) DNA transcription.
From a patient point of view, the most important property of an antimicrobial agent is its selective toxicity, i.e., that the agent acts in some way that inhibits or kills bacterial pathogens but has little or no toxic effect on the patient.
Characteristics of Antibiotics
Antibiotics may have a cidal (killing) effect or a static (inhibitory) effect on a range of microbes. The range of bacteria or other microorganisms that is affected by a certain antibiotic is expressed as its spectrum of action. Antibiotics effective against procaryotes that kill or inhibit a wide range of Gram-positive and Gram-negative bacteria are said to be broad spectrum. If effective mainly against Gram-positive or Gram-negative bacteria, they are narrow spectrum. If effective against a single organism or disease, they are referred to as limited spectrum.
A clinically-useful antibiotic should have as many of these characteristics as possible.
-It should have a wide spectrum of activity with the ability to destroy or inhibit many different species of pathogenic organisms.
-It should have a wide spectrum of activity with the ability to destroy or inhibit many different species of pathogenic organisms.
-It should be nontoxic to the host and without undesirable side effects.
-It should be nonallergenic to the host.
-It should not eliminate the normal flora of the host.
-It should be able to reach the part of the human body where the infection is occurring.
-It should be inexpensive and easy to produce.
-It should be chemically-stable (have a long shelf-life).
-Microbial resistance is uncommon and unlikely to develop.
Kinds of Antimicrobial Agents and their Primary Modes of Action
The table below is a summary of thetypes or classes of antibiotics and their properties including their biological source, spectrum and mode of action.
Classes of Antibiotics and their Properties| Chemical class | Examples | Biological source | Spectrum (effective against) | Mode of action | |
| Beta-lactams (penicillins and cephalosporins) | Penicillin G, Cephalothin | Penicillium notatum andCephalosporiumspecies | Gram-positive bacteria | Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly | |
| Semisynthetic beta-lactams | Ampicillin, Amoxicillin | Gram-positive and Gram-negative bacteria | Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly | ||
| Clavulanic Acid | Augmentin is clavulanic acid plus Amoxicillin | Streptomyces clavuligerus | Gram-positive and Gram-negative bacteria | Inhibitor of bacterial beta-lactamases | |
| Monobactams | Aztreonam | Chromobacterium violaceum | Gram-positive and Gram-negative bacteria | Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly | |
| Carboxypenems | Imipenem | Streptomyces cattleya | Gram-positive and Gram-negative bacteria | Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly | |
| Aminoglycosides | Streptomycin | Streptomyces griseus | Gram-positive and Gram-negative bacteria | Inhibits translation (protein synthesis) | |
| Gentamicin | Micromonosporaspecies | Gram-positive and Gram-negative bacteria esp.Pseudomonas | Inhibits translation (protein synthesis) | ||
| Glycopeptides | Vancomycin | Amycolatopsis orientalisNocardia orientalis(formerly designated) | Gram-positive bacteria, esp.Staphylococcus aureus | Inhibits steps in murein (peptidoglycan) biosynthesis and assembly | |
| Lincomycins | Clindamycin | Streptomyces lincolnensis | Gram-positive and Gram-negative bacteria esp. anaerobicBacteroides | Inhibits translation (protein synthesis) | |
| Macrolides | Erythromycin, Azithromycin | Streptomyces erythreus | Gram-positive bacteria, Gram-negative bacteria not enterics,Neisseria, Legionella, Mycoplasma | Inhibit translation (protein synthesis) | |
| Polypeptides | Polymyxin | Bacillus polymyxa | Gram-negative bacteria | Damages cytoplasmic membranes | |
| Bacitracin | Bacillus subtilis | Gram-positive bacteria | Inhibits steps in murein (peptidoglycan) biosynthesis and assembly | ||
| Polyenes | Amphotericin | Streptomyces nodosus | Fungi (Histoplasma) | Inactivate membranes containing sterols | |
| Nystatin | Streptomyces noursei | Fungi (Candida) | Inactivate membranes containing sterols | ||
| Rifamycins | Rifampicin | Streptomyces mediterranei | Gram-positive and Gram-negative bacteria,Mycobacterium tuberculosis | Inhibits transcription (bacterial RNA polymerase) | |
| Tetracyclines | Tetracycline | Streptomycesspecies | Gram-positive and Gram-negative bacteria, Rickettsias | Inhibit translation (protein synthesis) | |
| Semisynthetic tetracycline | Doxycycline | Gram-positive and Gram-negative bacteria, RickettsiasEhrlichia,Borrelia | Inhibit translation (protein synthesis) | ||
| Chloramphenicol | Chloramphenicol | Streptomyces venezuelae | Gram-positive and Gram-negative bacteria | Inhibits translation (protein synthesis) | |
| Quinolones | Nalidixic acid | synthetic | Mainly Gram-negative bacteria | Inhibits DNA replication | |
| Fluoroquinolones | Ciprofloxacin | synthetic | Gram-negative and some Gram-positive bacteria (Bacillus anthracis) | Inhibits DNA replication | |
| Growth factor analogs | Sulfanilamide, Gantrisin, Trimethoprim | synthetic | Gram-positive and Gram-negative bacteria | Inhibits folic acid metabolism (anti-folate) | |
| Isoniazid (INH) | synthetic | Mycobacterium tuberculosis | Inhibits mycolic acid synthesis; analog of pyridoxine (Vit B6) | ||
| para-aminosalicylic acid (PAS) | synthetic | Mycobacterium tuberculosis | Anti-folate |
Antimicrobial Agents Used in the Treatment of Infectious DiseaseExamination of the foregoing table reveals that there are a handful of fundamental ways that antibacterial antibiotics work as therapeutic agents. Recall that the target of an antibiotic should be unique to the bacterium and not found, or not accessible to the antibiotic, in the patient. These are the most important targets in bacteria that have been exploited so far.
1. Attack bacterial cell wall synthesis. Bacteria have murein in their cell walls, not found in the host, and murein (peptidoglycan) is essential to the viability of the bacterium.
2. Interfere with protein synthesis. Attack is almost always ate the level of translation using 70S ribosomes in the translation machinery. 70S cytoplasmic ribosomes are absent in eucaryotes.
3. Interference with nucleic acid synthesis (RNA and DNA), which exploits differences between RNA polymerases and DNA replication strategies in bacteria and eucaryotes.
4. Inhibition of an essential metabolic pathway that exists in the bacterium but does not exist in the host. This is usually brought about through the use of competitive chemical analogs for bacterial enzymatic reactions.
5. Membrane inhibition or disruption doesn't work too well because of the similarities between eucaryotic and bacterial membranes. However, the outer membrane of Gram-negative bacteria is a reasonable point of attack and some membrane inhibitors are included in the discussion below.
Cell wall synthesis inhibitors
Chemical structures of some beta-lactam antibiotics. Clockwise: penicillin, cephalosporin, monobactam, carbapenem. Note the characteristic structure of the beta lactam ring.
The semisynthetic beta-lactam, amoxicillin. Amoxicillin is usually the drug of choice within the class because it is better absorbed following oral administration than other beta-lactam antibiotics. It is susceptible to degradation by bacterial beta-lactamase enzymes so it may be given with calvulanic acid (below) to decrease its susceptibility. It is used against a wide range of Gram-positive bacteria, including Streptococcus pyogenes, penicillin-sensitive Streptococcus pneumoniae, non beta-lactamase producing strains of Staphylococcus aureus andEnterococcus faecalis. Susceptible Gram-negative organisms include non beta-lactamase producing strains of Haemophilus influenzae, Neisseria gonorrhoeaeand N. meningitidis.
Clavulanic acid is a chemical sometimes added to a semisynthetic penicillin preparation. Thus, amoxicillin plus clavulanate is clavamox or augmentin. The clavulanate is not an antimicrobial agent. It inhibits beta lactamase enzymes and has given extended life to penicillinase-sensitive beta lactams.
The structure of calvulanic acid. Clavulanic acid is not an antibiotic. It is a beta-lactamase inhibitor sometimes combined with semisynthetic beta lactam antibiotics to overcome resistance in bacteria that produce beta-lactamase enzymes, which otherwise inactivate the antibiotic. Most commonly it is combined with amoxicillin (above) as Augmentin (trade name) or the veterinary preparation, clavamox.
The core structure of cephalosporin. Substituent groups added at position X on the six-membered ring generates variants of the antibiotic.
Two other classes of beta lactams are the carbapenems and monobactams. The latter are particularly useful for the treatment of allergic individuals. A person who becomes allergic to penicillin usually becomes allergic to the cephalosporins and the carbapenems as well. Such individuals can still be treated with the monobactams, which are structurally different so as not to induce allergy.
Aztreonam is a synthetic monocyclic beta lactam antibiotic (a monobactam) originally isolated from the bacterium Chromobacterium violaceum. It is not useful against Gram-positive bacteria but it has strong activity against a wide range of susceptible Gram-negative bacteria, including Pseudomonas aeruginosa, E. coli, Haemophilus and Klebsiella.
Bacitracin is a polypeptide antibiotic produced by Bacillus species. It prevents cell wall growth by inhibiting the release of the muropeptide subunits of peptidoglycan from the lipid carrier molecule that carries the subunit to the outside of the membrane. Teichoic acid synthesis, which requires the same carrier, is also inhibited. Bacitracin has a high toxicity which precludes its systemic use. It is present in many topical antibiotic preparations, and since it is not absorbed by the gut, it is given to "sterilize" the bowel prior to surgery.
Bacitracin is a polypeptide antibiotic produced by the licheniformis group ofBacillus subtilis var. Tracy. It is effective used topically, primarily against Gram-positive bacteria. It is used in ointment or cream form for topical treatment of a variety of localized skin and eye infections, as well as for the prevention of wound infections. A popular brand name Neosporin, contains bacitracin, neomycin and polymyxin B.
Cell membrane inhibitors
Polymyxin B. Polymyxins are cationic detergent antibiotics, with a general structure of a cyclic peptide with a long hydrophobic tail. They disrupt the structure of the bacterial cell membrane by interacting with its phospholipids. Polymyxins have a bactericidal effect on Gram-negative bacilli, especially on Pseudomonas and coliform bacteria. Polymyxin antibiotics are highly neurotoxic and nephrotoxic, and very poorly absorbed from the gastrointestinal tract. Polymyxins also have antifungal activity.
1. Attack bacterial cell wall synthesis. Bacteria have murein in their cell walls, not found in the host, and murein (peptidoglycan) is essential to the viability of the bacterium.
2. Interfere with protein synthesis. Attack is almost always ate the level of translation using 70S ribosomes in the translation machinery. 70S cytoplasmic ribosomes are absent in eucaryotes.
3. Interference with nucleic acid synthesis (RNA and DNA), which exploits differences between RNA polymerases and DNA replication strategies in bacteria and eucaryotes.
4. Inhibition of an essential metabolic pathway that exists in the bacterium but does not exist in the host. This is usually brought about through the use of competitive chemical analogs for bacterial enzymatic reactions.
5. Membrane inhibition or disruption doesn't work too well because of the similarities between eucaryotic and bacterial membranes. However, the outer membrane of Gram-negative bacteria is a reasonable point of attack and some membrane inhibitors are included in the discussion below.
Cell wall synthesis inhibitors
Cell wall synthesis inhibitors generally inhibit some step in the synthesis of bacterial peptidoglycan. They exert their selective toxicity against bacteria because humans cells lack cell walls.
Beta lactam antibiotics. Chemically, these antibiotics contain a 4-membered beta lactam ring. They are the products of two genera of fungi, Penicillium andCephalosporium, and are correspondingly represented by the penicillins andcephalosporins.
Chemical structures of some beta-lactam antibiotics. Clockwise: penicillin, cephalosporin, monobactam, carbapenem. Note the characteristic structure of the beta lactam ring.
The beta lactam antibiotics are stereochemically related to D-alanyl-D-alanine, which is a substrate for the last step in peptidoglycan synthesis, the final cross-linking between between peptide side chains. Penicillins bind to and inhibit the carboxypeptidase and transpeptidase enzymes that are required for this step in peptidoglycan biosynthesis. Beta lactam antibiotics are bactericidal and require that cells be actively growing in order to exert their toxicity.
Different beta lactams differ in their spectrum of activity and their effect on Gram-negative rods, as well as their toxicity, stability in the human body, rate of clearance from blood, whether they can be taken orally, ability to cross the blood-brain barrier, and susceptibility to bacterial beta-lactamases.
Natural penicillins, such as penicillin G or penicillin V (benzyl penicillin), are produced by fermentation of Penicillium chrysogenum. They are effective against streptococci, gonococci and staphylococci, except where resistance has developed. They are considered narrow spectrum since they are not effective against Gram-negative rods.
Penicillin G (Benzylpenicillin) is typically given by parenteral administration because it is unstable in the acid of the stomach. However, this achieves higher tissue concentrations than orally-administered penicillins and this increases its antibacterial potential. "PenG" may be used in treatment of bacterial endocarditis, gonorrhea, syphilis, meningitis, and pneumonia.
Semisynthetic penicillins first appeared in 1959. A mold produces the main part of the molecule (6-aminopenicillanic acid), which can be modified chemically by the addition of side chains. Many of these compounds have been developed to have distinct benefits or advantages over penicillin G, such as increased spectrum of activity (effectiveness against Gram-negative rods), resistance to penicillinase, effectiveness when administered orally, etc.; amoxicillin andampicillin have broadened spectra against Gram-negative bacteria and are effective orally; methicillin is penicillinase-resistant.
The semisynthetic beta-lactam, amoxicillin. Amoxicillin is usually the drug of choice within the class because it is better absorbed following oral administration than other beta-lactam antibiotics. It is susceptible to degradation by bacterial beta-lactamase enzymes so it may be given with calvulanic acid (below) to decrease its susceptibility. It is used against a wide range of Gram-positive bacteria, including Streptococcus pyogenes, penicillin-sensitive Streptococcus pneumoniae, non beta-lactamase producing strains of Staphylococcus aureus andEnterococcus faecalis. Susceptible Gram-negative organisms include non beta-lactamase producing strains of Haemophilus influenzae, Neisseria gonorrhoeaeand N. meningitidis.
Clavulanic acid is a chemical sometimes added to a semisynthetic penicillin preparation. Thus, amoxicillin plus clavulanate is clavamox or augmentin. The clavulanate is not an antimicrobial agent. It inhibits beta lactamase enzymes and has given extended life to penicillinase-sensitive beta lactams.
The structure of calvulanic acid. Clavulanic acid is not an antibiotic. It is a beta-lactamase inhibitor sometimes combined with semisynthetic beta lactam antibiotics to overcome resistance in bacteria that produce beta-lactamase enzymes, which otherwise inactivate the antibiotic. Most commonly it is combined with amoxicillin (above) as Augmentin (trade name) or the veterinary preparation, clavamox.
Although nontoxic, penicillins occasionally cause death when administered to persons who are allergic to them. In the U.S. there are 300 - 500 deaths annually due to penicillin allergy. In allergic individuals the beta lactam molecule attaches to a serum protein and initiates an IgE-mediated inflammatory response.
Cephalosporins are beta lactam antibiotics with a similar mode of action to penicillins. They are produced by species of Cephalosporium molds. The have a low toxicity and a somewhat broader spectrum than natural penicillins. They are often used as penicillin substitutes against Gram-negative bacteria and in surgical prophylaxis. They are subject to degradation by some bacterial beta-lactamases, but they tend to be resistant to beta-lactamases from S. aureus.
The core structure of cephalosporin. Substituent groups added at position X on the six-membered ring generates variants of the antibiotic.
Two other classes of beta lactams are the carbapenems and monobactams. The latter are particularly useful for the treatment of allergic individuals. A person who becomes allergic to penicillin usually becomes allergic to the cephalosporins and the carbapenems as well. Such individuals can still be treated with the monobactams, which are structurally different so as not to induce allergy.
Aztreonam is a synthetic monocyclic beta lactam antibiotic (a monobactam) originally isolated from the bacterium Chromobacterium violaceum. It is not useful against Gram-positive bacteria but it has strong activity against a wide range of susceptible Gram-negative bacteria, including Pseudomonas aeruginosa, E. coli, Haemophilus and Klebsiella.
Bacitracin is a polypeptide antibiotic produced by Bacillus species. It prevents cell wall growth by inhibiting the release of the muropeptide subunits of peptidoglycan from the lipid carrier molecule that carries the subunit to the outside of the membrane. Teichoic acid synthesis, which requires the same carrier, is also inhibited. Bacitracin has a high toxicity which precludes its systemic use. It is present in many topical antibiotic preparations, and since it is not absorbed by the gut, it is given to "sterilize" the bowel prior to surgery.
Bacitracin is a polypeptide antibiotic produced by the licheniformis group ofBacillus subtilis var. Tracy. It is effective used topically, primarily against Gram-positive bacteria. It is used in ointment or cream form for topical treatment of a variety of localized skin and eye infections, as well as for the prevention of wound infections. A popular brand name Neosporin, contains bacitracin, neomycin and polymyxin B.
Cycloserine inhibits the early stages of murein synthesis where D-alanyl-D-alanine is added to the growing peptide side chain. The antibiotic resembles D-alanine in spatial structure, and it competitively inhibits the racemase reaction that converts L-alanine to D-alanine and the synthetase reaction that joins two D-alanine molecules. The affinity of cycloserine for these enzymes is about a hundred times greater than that of D-alanine. Cycloserine enters bacterial cells by means of an active transport system for glycine and can reach a relatively high intracellular concentration. This concentrating effect, along with its high affinity for susceptible enzymes, enables cycloserine to function as a very effective antimicrobial agent. However, it is fairly toxic and has limited use as a secondary drug for tuberculosis.
Cycloserine is an oral broad spectrum antibiotic effective against tuberculosis, by inhibiting cell wall synthesis of TB bacilli at the early stages of peptidoglycan synthesis. For the treatment against tuberculosis, it is classified as a second line drug.
Cycloserine is an oral broad spectrum antibiotic effective against tuberculosis, by inhibiting cell wall synthesis of TB bacilli at the early stages of peptidoglycan synthesis. For the treatment against tuberculosis, it is classified as a second line drug.
Glycopeptides, such as the antibiotic vancomycin, inhibit both transglycosylation and transpeptidation reactions during peptidoglycan assembly. They bind to the muropeptide subunit as it is transferred out of the cell cytoplasm and inhibit subsequent polymerization reactions. Vancomycin is not effective against Gram-negative bacteria because it cannot penetrate their outer membrane. However, it has become important in clinical usage for treatment of infections by strains of Staphylococcus aureus that are resistant to virtually all other antibiotics (MRSA).
Vancomycin is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of vancomycin-resistant organisms means that it is increasingly being displaced from this role by linezolid and the carbapenems.
Cell membrane inhibitors
These antibiotics disorganize the structure or inhibit the function of bacterial membranes. The integrity of the cytoplasmic and outer membranes is vital to bacteria, and compounds that disorganize the membranes rapidly kill the cells. However, due to the similarities in phospholipids in eubacterial and eucaryotic membranes, this action is rarely specific enough to permit these compounds to be used systemically. The only antibacterial antibiotics of clinical importance that act by this mechanism are the polymyxins, produced by Bacillus polymyxa. Polymyxin is effective mainly against Gram-negative bacteria and is usually limited to topical usage. Polymyxins bind to membrane phospholipids and thereby interfere with membrane function. Polymyxin is occasionally given for urinary tract infections caused by Pseudomonas strains that are gentamicin, carbenicillin and tobramycin resistant. The balance between effectiveness and damage to the kidney and other organs is dangerously close, and the drug should only be given under close supervision in the hospital.
Polymyxin B. Polymyxins are cationic detergent antibiotics, with a general structure of a cyclic peptide with a long hydrophobic tail. They disrupt the structure of the bacterial cell membrane by interacting with its phospholipids. Polymyxins have a bactericidal effect on Gram-negative bacilli, especially on Pseudomonas and coliform bacteria. Polymyxin antibiotics are highly neurotoxic and nephrotoxic, and very poorly absorbed from the gastrointestinal tract. Polymyxins also have antifungal activity.
Protein synthesis inhibitors
Many therapeutically useful antibiotics owe their action to inhibition of some step in the complex process of protein synthesis. Their attack is always at one of the events occurring on the ribosome and never at the stage of amino acid activation or attachment to a particular tRNA. Most have an affinity or specificity for 70S (as opposed to 80S) ribosomes, and they achieve their selective toxicity in this manner. The most important antibiotics with this mode of action are thetetracyclines, chloramphenicol, the macrolides (e.g. erythromycin) and theaminoglycosides (e.g. streptomycin).
The aminoglycosides are products of Streptomyces species and are represented by streptomycin, kanamycin, tobramycin and gentamicin. These antibiotics exert their activity by binding to bacterial ribosomes and preventing the initiation of protein synthesis.
Streptomycin binds to 30S subunit of the bacterial ribosome, specifically to the S12 protein which is involved in the initiation of protein synthesis. Experimentally, streptomycin has been shown to prevent the initiation of protein synthesis by blocking the binding of initiator N-formylmethionine tRNA to the ribosome. It also prevents the normal dissociation of ribosomes into their subunits, leaving them mainly in their 70S form and preventing the formation of polysomes. The overall effect of streptomycin seems to be one of distorting the ribosome so that it no longer can carry out its normal functions. This evidently accounts for its antibacterial activity but does not explain its bactericidal effects, which distinguishes streptomycin and other aminoglycosides from most other protein synthesis inhibitors.
Streptomycin is the first aminoglycoside antibiotic to be discovered, and was the first antibiotic to be used in treatment of tuberculosis. It was discovered in 1943, in the laboratory of Selman Waksman at Rutgers University. Waksman and his laboratory discovered several antibiotics, including actinomycin, streptomycin, and neomycin. Streptomycin is derived from the bacterium, Streptomyces griseus. Streptomycin stops bacterial growth by inhibiting protein synthesis. Specifically, it binds to the 16S rRNA of the bacterial ribosome, interfering with the binding of formyl-methionyl-tRNA to the 30S subunit. This prevents initiation of protein synthesis.
Streptomycin is the first aminoglycoside antibiotic to be discovered, and was the first antibiotic to be used in treatment of tuberculosis. It was discovered in 1943, in the laboratory of Selman Waksman at Rutgers University. Waksman and his laboratory discovered several antibiotics, including actinomycin, streptomycin, and neomycin. Streptomycin is derived from the bacterium, Streptomyces griseus. Streptomycin stops bacterial growth by inhibiting protein synthesis. Specifically, it binds to the 16S rRNA of the bacterial ribosome, interfering with the binding of formyl-methionyl-tRNA to the 30S subunit. This prevents initiation of protein synthesis.
Kanamycin and tobramycin have been reported to bind to the ribosomal 30S subunit and to prevent it from joining to the 50S subunit during protein synthesis. They may have a bactericidal effect because this leads to cytoplasmic accumulation of dissociated 30S subunits, which is apparently lethal to the cells.
Aminoglycosides have been used against a wide variety of bacterial infections caused by Gram-positive and Gram-negative bacteria. Streptomycin has been used extensively as a primary drug in the treatment of tuberculosis. Gentamicinis active against many strains of Gram-positive and Gram-negative bacteria, including some strains of Pseudomonas aeruginosa. Kanamycin is active at low concentrations against many Gram-positive bacteria, including penicillin-resistant staphylococci. Gentamicin and Tobramycin are mainstays for treatment ofPseudomonas infections. An unfortunate side effect of aminoglycosides has tended to restrict their usage: prolonged use is known to impair kidney function and cause damage to the auditory nerves leading to deafness.
Gentamicin is an aminoglycoside antibiotic, used mostly to treat Gram-negative infections. However, it is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila infections. It is synthesized byMicromonospora, a genus of Gram-positive bacteria widely distributed in water and soil. Like all aminoglycosides, when gentamicin is given orally, it is not systemically active because it is not absorbed to any appreciable extent from the small intestine. It is useful in treatment of infections caused by Pseudomonas aeruginosa.The tetracyclines consist of eight related antibiotics which are all natural products of Streptomyces, although some can now be produced semisynthetically or synthetically. Tetracycline, chlortetracycline anddoxycycline are the best known. The tetracyclines are broad-spectrum antibiotics with a wide range of activity against both Gram-positive and Gram-negative bacteria. Pseudomonas aeruginosa is less sensitive but is generally susceptible to tetracycline concentrations that are obtainable in the bladder. The tetracyclines act by blocking the binding of aminoacyl tRNA to the A site on the ribosome. Tetracyclines inhibit protein synthesis on isolated 70S or 80S (eucaryotic) ribosomes, and in both cases, their effect is on the small ribosomal subunit. However, most bacteria possess an active transport system for tetracycline that will allow intracellular accumulation of the antibiotic at concentrations 50 times as great as that in the medium. This greatly enhances its antibacterial effectiveness and accounts for its specificity of action, since an effective concentration cannot be accumulated in animal cells. Thus a blood level of tetracycline which is harmless to animal tissues can halt protein synthesis in invading bacteria.
The tetracyclines have a remarkably low toxicity and minimal side effects when taken by animals. The combination of their broad spectrum and low toxicity has led to their overuse and misuse by the medical community and the wide-spread development of resistance has reduced their effectiveness. Nonetheless, tetracyclines still have some important uses, such as the use of doxycycline in the treatment of Lyme disease.
Some newly discovered members of the tetracycline family (e.g. chelocardin) have been shown to act by inserting into the bacterial membrane, not by inhibiting protein synthesis.
The tetracycline core structure. The tetracyclines are a large family of antibiotics that were discovered as natural products of Streptomyces bacteria beginning in the late 1940s. Tetracycline sparked the development of many chemically altered antibiotics and in doing so has proved to be one of the most important discoveries made in the field of antibiotics. It is a classic "broad-spectrum antibiotic" used to treat infections caused by Gram-positive and Gram-negative bacteria and some protozoa.
Doxycycline is a semisynthetic tetracycline developed in the 1960s. It is frequently used to treat chronic prostatitis, sinusitis, syphilis, chlamydia, pelvic inflammatory disease, acne and rosacea. In addition, it is used in the treatment and prophylaxis of anthrax and in prophylaxis against malaria. It is also effective against Yersinia pestis (the infectious agent of bubonic plague) and is prescribed for the treatment of Lyme disease, ehrlichiosis and Rocky Mountain spotted fever. Because doxycycline is one of the few medications that is effective in treating Rocky Mountain spotted fever (with the next best alternative being chloramphenicol), it is indicated even for use in children for this illness.
Chloramphenicol is a protein synthesis inhibitor that has a broad spectrum of activity but it exerts a bacteriostatic effect. It is effective against intracellular parasites such as the rickettsiae. Unfortunately, aplastic anemia develops in a small proportion (1/50,000) of patients. Chloramphenicol was originally discovered and purified from the fermentation of a Streptomyces species, but currently it is produced entirely by chemical synthesis. Chloramphenicol inhibits the bacterial enzyme peptidyl transferase, thereby preventing the growth of the polypeptide chain during protein synthesis.
Chemical structure of chloramphenicol
Chloramphenicol is entirely selective for 70S ribosomes and does not affect 80S ribosomes. Its unfortunate toxicity towards the small proportion of patients who receive it is in no way related to its effect on bacterial protein synthesis. However, since mitochondria originated from procaryotic cells and have 70S ribosomes, they are subject to inhibition by some of the protein synthesis inhibitors including chloramphenicol. This likely explains the toxicity of chloramphenicol. The eucaryotic cells most likely to be inhibited by chloramphenicol are those undergoing rapid multiplication, thereby rapidly synthesizing mitochondria. Such cells include the blood forming cells of the bone marrow, the inhibition of which could present as aplastic anemia. Chloramphenicol was once a highly prescribed antibiotic and a number of deaths from anemia occurred before its use was curtailed. Now it is seldom used in human medicine except in life-threatening situations (e.g. typhoid fever).
The macrolide family of antibiotics is characterized by structures that contain large lactone rings linked through glycoside bonds with amino sugars. The most important members of the group are erythromycin and oleandomycin.Erythromycin is active against most Gram-positive bacteria, Neisseria,Legionella and Haemophilus, but not against the Enterobacteriaceae. Macrolides inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit. Binding inhibits elongation of the protein by peptidyl transferase or prevents translocation of the ribosome or both. Macrolides are bacteriostatic for most bacteria but are cidal for a few Gram-positive bacteria.
Chemical structure of a macrolide antibiotic, erythromycin.
Azithromycin, shown above, is a subclass of macrolide antibiotics. Azithromycin is one of the world's best-selling antibiotics. It is s derived from erythromycin, but it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring, thus making the lactone ring 15-membered. Azithromycin is used to treat certain bacterial infections, most often bacteria causing middle ear infections, tonsillitis, throat infections, laryngitis, bronchitis, pneumonia and sinusitis. It is also effective against certain sexually transmitted diseases, such as non-gonococcal urethritis and cervicitis.
Lincomycin and clindamycin are a miscellaneous group of protein synthesis inhibitors with activity similar to the macrolides. Lincomycin has activity against Gram-positive bacteria and some Gram-negative bacteria (Neisseria, H. influenzae). Clindamycin is a derivative of lincomycin with the same range of antimicrobial activity, but it is considered more effective. It is frequently used as a penicillin substitute and is effective against Gram-negative anaerobes (e.g.Bacteroides).
Clindamycin is a lincosamide antibiotic. It is usually used to treat infections with anaerobic bacteria but can also be used to treat some protozoal diseases, such as malaria. It is a common topical treatment for acne, and can be useful against some methicillin-resistant Staphylococcus aureus (MRSA) infections. The most severe common adverse effect of clindamycin is Clostridium difficile-associated diarrhea (the most frequent cause of pseudomembranous colitis). Although this side-effect occurs with almost all antibiotics, including beta-lactam antibiotics, it is classically linked to clindamycin use.
Effects on Nucleic Acids
Some antibiotics and chemotherapeutic agents affect the synthesis of DNA or RNA, or can bind to DNA or RNA so that their messages cannot be read. Either case, of course, can block the growth of cells. The majority of these drugs are unselective, however, and affect animal cells and bacterial cells alike and therefore have no therapeutic application. Two nucleic acid synthesis inhibitors which have selective activity against procaryotes and some medical utility are the quinolones and rifamycins.
Nalidixic acid is a synthetic chemotherapeutic agent that has activity mainly against Gram-negative bacteria. Nalidixic acid belongs to a group of compounds called quinolones. Nalidixic acid is a bactericidal agent that binds to the DNA gyrase enzyme (topoisomerase) which is essential for DNA replication and allows supercoils to be relaxed and reformed. Binding of the drug inhibits DNA gyrase activity.
Some quinolones penetrate macrophages and neutrophils better than most antibiotics and are thus useful in treatment of infections caused by intracellular parasites. However, the main use of nalidixic acid is in treatment of lower urinary tract infections (UTI). The compound is unusual in that it is effective against several types of Gram-negative bacteria such as E. coli, Enterobacter aerogenes, K. pneumoniae and Proteus species which are common causes of UTIs. It is not usually effective against Pseudomonas aeruginosa, and Gram-positive bacteria may be resistant. Some quinolones have a broadened spectrum against Gram-positive bacteria. The fluoroquinolone, Cipro. (ciprofloxacin) was recently touted as the drug of choice for treatment and prophylaxis of anthrax, which is caused by a Gram-positive bacillus, Bacillus anthracis.
Ciprofloxacin (cipro), a fluoroquinolone is a broad-spectrum antimicrobial agent that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, which is an enzyme necessary to separate replicated DNA, and thereby inhibits cell division.
The rifamycins are a comparatively new group of antibiotics, also the products of Streptomyces species. Rifampicin is a semisynthetic derivative of rifamycinthat is active against Gram-positive bacteria (including Mycobacterium tuberculosis) and some Gram-negative bacteria. Rifampicin acts quite specifically on the bacterial RNA polymerase and is inactive towards DNA polymerase or RNA polymerase from animal cells. The antibiotic binds to the beta subunit of the polymerase and apparently blocks the entry of the first nucleotide which is necessary to activate the polymerase, thereby blocking mRNA synthesis. It has been found to have greater bactericidal effect against M. tuberculosis than other anti-tuberculosis drugs, and it has largely replaced isoniazid as one of the front-line drugs used to treat the disease, especially when isoniazid resistance is indicated. It is effective orally and penetrates the cerebrospinal fluid so it is useful for treatment of bacterial meningitis.
Rifampicin (or rifampin) is a bactericidal antibiotic from the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica (formerly known as Amycolatopsis mediterranei and Streptomyces mediterranei). Rifampicin is typically used to treat Mycobacterium infections, including tuberculosis and leprosy; and also has a role in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in combination with fusidic acid. It is used in prophylactic therapy against Neisseria meningitidis (meningococcal) infection. It is also used to treat infection by Listeria monocytogenes, Neisseria gonorrhoeae, Haemophilus influenzae and Legionella pneumophila.
Some quinolones penetrate macrophages and neutrophils better than most antibiotics and are thus useful in treatment of infections caused by intracellular parasites. However, the main use of nalidixic acid is in treatment of lower urinary tract infections (UTI). The compound is unusual in that it is effective against several types of Gram-negative bacteria such as E. coli, Enterobacter aerogenes, K. pneumoniae and Proteus species which are common causes of UTIs. It is not usually effective against Pseudomonas aeruginosa, and Gram-positive bacteria may be resistant. Some quinolones have a broadened spectrum against Gram-positive bacteria. The fluoroquinolone, Cipro. (ciprofloxacin) was recently touted as the drug of choice for treatment and prophylaxis of anthrax, which is caused by a Gram-positive bacillus, Bacillus anthracis.
Ciprofloxacin (cipro), a fluoroquinolone is a broad-spectrum antimicrobial agent that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, which is an enzyme necessary to separate replicated DNA, and thereby inhibits cell division.
The rifamycins are a comparatively new group of antibiotics, also the products of Streptomyces species. Rifampicin is a semisynthetic derivative of rifamycinthat is active against Gram-positive bacteria (including Mycobacterium tuberculosis) and some Gram-negative bacteria. Rifampicin acts quite specifically on the bacterial RNA polymerase and is inactive towards DNA polymerase or RNA polymerase from animal cells. The antibiotic binds to the beta subunit of the polymerase and apparently blocks the entry of the first nucleotide which is necessary to activate the polymerase, thereby blocking mRNA synthesis. It has been found to have greater bactericidal effect against M. tuberculosis than other anti-tuberculosis drugs, and it has largely replaced isoniazid as one of the front-line drugs used to treat the disease, especially when isoniazid resistance is indicated. It is effective orally and penetrates the cerebrospinal fluid so it is useful for treatment of bacterial meningitis.
Rifampicin (or rifampin) is a bactericidal antibiotic from the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica (formerly known as Amycolatopsis mediterranei and Streptomyces mediterranei). Rifampicin is typically used to treat Mycobacterium infections, including tuberculosis and leprosy; and also has a role in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in combination with fusidic acid. It is used in prophylactic therapy against Neisseria meningitidis (meningococcal) infection. It is also used to treat infection by Listeria monocytogenes, Neisseria gonorrhoeae, Haemophilus influenzae and Legionella pneumophila.
Competitive Inhibitors
Many of the synthetic chemotherapeutic agents (synthetic antibiotics) arecompetitive inhibitors of essential metabolites or growth factors that are needed in bacterial metabolism. Hence, these types of antimicrobial agents are sometimes referred to as anti-metabolites or growth factor analogs, since they are designed to specifically inhibit an essential metabolic pathway in the bacterial pathogen. At a chemical level, competitive inhibitors are structurally similar to a bacterial growth factor or metabolite, but they do not fulfill their metabolic function in the cell. Some are bacteriostatic and some are bactericidal. Their selective toxicity is based on the premise that the bacterial pathway does not occur in the host.
Sulfonamides were introduced as chemotherapeutic agents by Domagk in 1935, who showed that one of these compounds (prontosil) had the effect of curing mice with infections caused by beta-hemolytic streptococci. Chemical modifications of the compound sulfanilamide gave rise to compounds with even higher and broader antibacterial activity. The resulting sulfonamides have broadly similar antibacterial activity, but differ widely in their pharmacological actions. Bacteria which are almost always sensitive to the sulfonamides includeStreptococcus pneumoniae, beta-hemolytic streptococci and E. coli. The sulfonamides have been extremely useful in the treatment of uncomplicated UTI caused by E. coli, and in the treatment of meningococcal meningitis (because they cross the blood-brain barrier).
The sulfonamides (e.g. Gantrisin and Trimethoprim) are inhibitors of the bacterial enzymes required for the synthesis of tetrahydofolic acid (THF), the vitamin form of folic acid essential for 1-carbon transfer reactions. Sulfonamides are structurally similar to para aminobenzoic acid (PABA), the substrate for the first enzyme in the THF pathway, and they competitively inhibit that step. Trimethoprim is structurally similar to dihydrofolate (DHF) and competitively inhibits the second step in THF synthesis mediated by the DHF reductase. Animal cells do not synthesize their own folic acid but obtain it in a preformed fashion as a vitamin. Since animals do not make folic acid, they are not affected by these drugs, which achieve their selective toxicity for bacteria on this basis.
The chemical structures of sulfanilamide and para-aminobenzoic acid (PABA). In bacteria, sulfanilamide acts as a competitive inhibitor of the enzyme dihydropteroate synthetase, DHPS, which catalyses the conversion of PABA to dihydropteroate, a key step in folate synthesis. Folate is necessary for the cell to synthesize nucleic acids (DNA and RNA), and in its absence, cells will be unable to divide. Hence, sulfanilamide and other sulfonamides exhibit a bacteriostatic rather than bactericidal effect.
Three additional synthetic chemotherapeutic agents have been used in the treatment of tuberculosis: isoniazid (INH), para-aminosalicylic acid (PAS), and ethambutol. The usual strategy in the treatment of tuberculosis has been to administer a single antibiotic (historically streptomycin, but now, most commonly, rifampicin is given) in conjunction with INH and ethambutol. Since the tubercle bacillus rapidly develops resistance to the antibiotic, ethambutol and INH are given to prevent outgrowth of a resistant strain. It must also be pointed out that the tubercle bacillus rapidly develops resistance to ethambutol and INH if either drug is used alone. Ethambutol inhibits incorporation of mycolic acids into the mycobacterial cell wall. Isoniazid has been reported to inhibit mycolic acid synthesis in mycobacteria and since it is an analog of pyridoxine (Vitamin B6) it may inhibit pyridoxine-catalyzed reactions as well. Isoniazid is activated by a mycobacterial peroxidase enzyme and destroys several targets in the cell. PAS is an anti-folate, similar in activity to the sulfonamides. PAS was once a primary anti-tuberculosis drug, but now it is a secondary agent, having been largely replaced by ethambutol.
Isoniazid is also called isonicotinyl hydrazine or INH. Isoniazid is a first-line anti-tuberculosis medication used in the prevention and treatment of tuberculosis. Isoniazid is never used on its own to treat active tuberculosis because resistance quickly develops.
Isoniazid is also called isonicotinyl hydrazine or INH. Isoniazid is a first-line anti-tuberculosis medication used in the prevention and treatment of tuberculosis. Isoniazid is never used on its own to treat active tuberculosis because resistance quickly develops.
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