18.4: Antimicrobial Agents
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Antimicrobial chemotherapy is the use of chemicals to inhibit or kill microorganisms in or on the host. Chemotherapy is based on selective toxicity. This means that the agent used must inhibit or kill the microorganism in question without seriously harming the host.
In order to be selectively toxic, a chemotherapeutic agent must interact with some microbial function or microbial structure that is either not present or is substantially different from that of the host. For example, in treating infections caused by prokaryotic bacteria, the agent may inhibit peptidoglycan synthesis or alter bacterial (prokaryotic) ribosomes. Human cells do not contain peptidoglycan and possess eukaryotic ribosomes. Therefore, the drug shows little if any effect on the host (selective toxicity). Eukaryotic microorganisms, on the other hand, have structures and functions more closely related to those of the host. As a result, the variety of agents selectively effective against eukaryotic microorganisms such as fungi and protozoans is small when compared to the number available against prokaryotes. Also keep in mind that viruses are not cells and, therefore, lack the structures and functions altered by antibiotics so antibiotics are not effective against viruses.
Based on their origin, there are 2 general classes of antimicrobial chemotherapeutic agents:
1. antibiotics: substances produced as metabolic products of one microorganism which inhibit or kill other microorganisms.
2. antimicrobial chemotherapeutic chemicals: chemicals synthesized in the laboratory which can be used therapeutically on microorganisms.
Today the distinction between the 2 classes is not as clear, since many antibiotics are extensively modified in the laboratory (semisynthetic) or even synthesized without the help of microorganisms.
Most of the major groups of antibiotics were discovered prior to 1955, and most antibiotic advances since then have come about by modifying the older forms. In fact, only 3 major groups of microorganisms have yielded useful antibiotics: the actinomycetes (filamentous, branching soil bacteria such as Streptomyces), bacteria of the genus Bacillus, and the saprophytic molds Penicillium and Cephalosporium.
To produce antibiotics, manufacturers inoculate large quantities of medium with carefully selected strains of the appropriate species of antibiotic-producing microorganism. After incubation, the drug is extracted from the medium and purified. Its activity is standardized and it is put into a form suitable for administration.
Some antimicrobial agents are cidal in action: they kill microorganisms (e.g., penicillins, cephalosporins, streptomycin, neomycin). Others are static in action: they inhibit microbial growth long enough for the body's own defenses to remove the organisms (e.g., tetracyclines, erythromycin, sulfonamides).
Antimicrobial agents also vary in their spectrum. Drugs that are effective against a variety of both Gram-positive and Gram-negative bacteria are said to be broad spectrum (e.g., tetracycline, streptomycin, cephalosporins, ampicillin, sulfonamides). Those effective against just Gram-positive bacteria, just Gram negative bacteria, or only a few species are termed narrow spectrum (e.g., penicillin G, erythromycin, clindamycin, gentamicin).
If a choice is available, a narrow spectrum is preferable since it will cause less destruction to the body's normal flora. In fact, indiscriminate use of broad spectrum antibiotics can lead to superinfection by opportunistic microorganisms, such as Candida (yeast infections) and Clostridium difficile (antibiotic-associated ulcerative colitis), when the body's normal flora is destroyed. Other dangers from indiscriminate use of antimicrobial chemotherapeutic agents include drug toxicity, allergic reactions to the drug, and selection for resistant strains of microorganisms.
Below are examples of commonly used antimicrobial chemotherapeutic agents arranged according to their mode of action:
1. Antimicrobial agents that inhibit peptidoglycan synthesis. Inhibition of peptidoglycan synthesis in actively-dividing bacteria results in osmotic lysis. (A list of common antimicrobial chemotherapeutic agents listed by both their generic and brand names and arranged by their mode of action can be found in Table 1.)
a. Penicillins (produced by the mold Penicillium)
There are several classes of penicillins:
1. Natural penicillins are highly effective against Gram-positive bacteria (and a very few Gram-negative bacteria) but are inactivated by the bacterial enzyme penicillinase. Examples include penicillin G, F, X, K, O, and V.
2. Semisynthetic penicillins are effective against Gram-positive bacteria but are not inactivated by penicillinase. Examples include methicillin, dicloxacillin, and nafcillin.
3. Semisynthetic broad-spectrum penicillins are effective against a variety of Gram-positive and Gram-negative bacteria but are inactivated by penicillinase. Examples include ampicillin, carbenicillin, oxacillin, azlocillin, mezlocillin, and piperacillin.
4. Semisynthetic broad-spectrum penicillins combined with beta lactamase inhibitors such as clavulanic acid and sulbactam. Although the clavulanic acid and sulbactam have no antimicrobial action of their own, they inhibits penicillinase thus protecting the penicillin from degradation. Examples include amoxicillin plus clavulanic acid, ticarcillin plus clavulanic acid, and ampicillin plus sulbactam.
b. Cephalosporins (produced by the mold Cephalosporium)
Cephalosporins are effective against a variety of Gram-positive and Gram-negative bacteria and are resistant to penicillinase (although some can be inactivated by other beta-lactamase enzymes similar to penicillinase). Four "generations" of cephalosporins have been developed over the years in an attempt to counter bacterial resistance.
1. First generation cephalosporins include cephalothin, cephapirin, and cephalexin.
2. Second generation cephalosporins include cefamandole, cefaclor, cefazolin, cefuroxime, and cefoxitin.
3. Third generation cephalosporins include cefotaxime, cefsulodin, cefetamet, cefixime, ceftriaxone, cefoperazone, ceftazidine, and moxalactam.
4. Fourth generation cephalosporins include cefepime and cefpirome.
c. Carbapenems: Carbapenems consist of a broad spectrum beta lactam antibiotic to inhibit peptidoglycan synthesis combined with cilastatin sodium, an agent which prevents degradation of the antibiotic in the kidneys. Examples include: imipenem, metropenem, ertapenem, and doripenem.
d. Monobactems: Monobactems are broad spectrum beta lactam antibiotics resistant to beta lactamase. An example is aztreonam.
e. Carbacephem: A synthetic cephalosporins. An example is loracarbef.
e. Glycopeptides (produced by the bacterium Streptomyces): Vancomycin and teichoplanin are glycopeptides that are effective against Gram-positive bacteria.
f. Bacitracin (produced by the bacterium Bacillus): Bacitracin is used topically against Gram-positive bacteria.
h. Fosfomycin (Monurol )
2. A few antimicrobial chemotherapeutic agents inhibit normal synthesis of the acid-fast cell wall of the genus Mycobacterium.
a. INH (isoniazid) appears to block the synthesis of mycolic acid, a key component of the acid-fast cell wall of mycobacteria.
b. Ethambutol interferes with the synthesis of the outer membrane of acid-fast cell walls.
3. Antimicrobial agents that alter the cytoplasmic membrane. Alteration of the cytoplasmic membrane of microorganisms results in leakage of cellular materials. (A list of common antimicrobial chemotherapeutic agents listed by both their generic and brand names and arranged by their mode of action can be found in Table 1.)
a. Polymyxins and colistins act as detergents and alter membrane permeability in Gram-negative bacteria. They cannot effectively diffuse through the thick peptidoglycan layer in Gram-positives.
b. Daptomycin disrupts the bacterial cytoplasmic membrane function by apparently binding to the membrane and causing rapid depolarization. This results on a loss of membrane potential and leads to inhibition of protein, DNA and RNA synthesis, resulting in bacterial cell death.
c. Pyrazinamide inhibits fatty acid synthesis in the membranes of Mycobacterium tuberculosis.
d . Amphotericin B, produced by the bacterium Streptomyces, is used for systemic fungal infections. It interferes with membrane permeability by interacting with membrane sterols called ergosterols and forming pores in the membrane causing cellular leakage.
e . Nystatin, produced by the bacterium Streptomyces, is used mainly for Candida yeast infections. It interferes with membrane permeability by interacting with membrane sterols called ergosterols and forming pores in the membrane causing cellular leakage.
f. Imidazoles, produced by the bacterium Streptomyces, are antifungal antibiotics used for yeast infections, dermatophytic infections, and systemic fungal infections. They interfere with the synthesis of ergosterol, the sterol in fungal cytoplasmic membranes, causing cellular leakage. Examples include clotrimazole, miconazole, ketoconazole, itraconazole, and fluconazole.
4 . Antimicrobial agents that inhibit protein synthesis. (A list of common antimicrobial chemotherapeutic agents listed by both their generic and brand names and arranged by their mode of action can be found in Table 1.)
These agents prevent bacteria from synthesizing structural proteins and enzymes.
a. Agents that block transcription (prevent the synthesis of mRNA off of DNA).
Rifampin or Rifampicin: rifadin, rifater combined with isoniazid and pyrazinamide , rimactane (produced by the bacterium Streptomyces). Rifaximins are effective against some Gram‑positive and Gram-negative bacteria and Mycobacterium tuberculosis.
b. Agents that block translation (alter bacterial ribosomes to prevent mRNA from being translated into proteins).
1. The aminoglycosides (streptomycin, neomycin, netilmicin, tobramycin, gentamicin, amikacin, etc.) bind irreversibly to the 16S rRNA in the 30S subunit of bacterial ribosomes interfering with the translation stage of protein syntheses. Although the exact mechanism of action is still uncertain, there is evidence that some prevent the transfer of the peptidyl tRNA from the A-site to the P-site, thus preventing the elongation of the polypeptide chain. Some aminoglycosides also appear to interfere with the proofreading process that helps assure the accuracy of translation. Possibly the antibiotics reduce the rejection rate for tRNAs that are near matches for the codon. This leads to misreading of the codons or premature termination of protein synthesis. Aminoglycosides may also interfere directly or indirectly with the function of the bacterial cytoplasmic membrane. Because of their toxicity, aminoglycosides are generally used only when other first line antibiotics are not effective.
2. The tetracyclines (tetracycline, doxycycline, demeclocycline, minocycline, etc.) bind reversibly to the 16S rRNA in the 30S ribosomal subunit interfering with the translation stage of protein synthese. They distort the ribosome in such a way that the anticodons of charged tRNAs cannot align properly with the codons of the mRNA Examples include tetracycline, minocycline, and doxycycline, produced by the bacterium Streptomyces. They are effective against a variety of Gram-positive and Gram-negative bacteria.
3. Lincomycin and clindamycin, produced by the bacterium Streptomyces, bind reversibly to the 23S rRNA in the 50s ribosomal subunit and block peptide bond formation during the translation stage of protein synthesis. Most are used against Gram-positive bacteria.
4. The macrolides (erythromycin, azithromycin, clarithromycin, dirithromycin, troleandomycin, etc.) bind reversibly to the 23S rRNA in the 50S subunit of bacterial ribosomes interfering with the translation stage of protein syntheses. They appear to inhibit elongation of the protein by preventing the enzyme peptidyltransferase from forming peptide bonds between the amino acids. They may also prevent the transfer of the peptidyl tRNA from the A-site to the P-site as the beginning peptide chain on the peptidyl tRNA adheres to the ribosome, creates friction, and blocks the exit tunnel of the 50S ribosomal subunit. Macrolides are used against Gram-positive bacteria and some Gram-negative bacteria.
5. The oxazolidinones (linezolid), following the first cycle of protein synthesis, interfere with translation sometime before the initiation phase. They appear to bind to the 50S ribosomal subunit and interfere with its binding to the initiation complex.
6. The streptoGramins (synercid, a combination of quinupristin and dalfopristin) bind to two different locations on the 23S rRNA in the 50S ribosomal subunit and work synergistically to block the translation stage of protein synthesis. There are reports that the streptoGramins may inhibit the attachment of the charged tRNA to the A-site or may block the peptide exit tunnel of the 50S ribosomal subunit.
5 . Antimicrobial agents that interfere with DNA synthesis. (A list of common antimicrobial chemotherapeutic agents listed by both their generic and brand names and arranged by their mode of action can be found in Table 1.)
a.The fluoroquinolones (norfloxacin, lomefloxacin, fleroxacin, ciprofloxacin, enoxacin, trovafloxacin, gatifloxacin, etc.) work by inhibiting one or more of a group of enzymes called topoisomerase, enzymes needed for supercoiling, replication, and separation of circular bacterial DNA. For example, DNA gyrase (topoisomerase II) catalyzes the negative supercoiling of the circular DNA found in bacteria. It is critical in bacterial DNA replication, DNA repair, transcription of DNA into RNA, and genetic recombination. Topoisomerase IV, on the other hand, is involved in the relaxation of the supercoiled circular DNA, enabling the separation of the interlinked daughter chromosomes at the end of bacterial DNA replication.
b. Sulfonamides and trimethoprim (synthetic chemicals): Co-trimoxazole is a combination of sulfamethoxazole and trimethoprim. Both of these drugs block enzymes in the bacteria pathway required for the synthesis of tetrahydrofolic acid, a cofactor needed for bacteria to make the nucleotide bases thymine, guanine, uracil, and adenine.
c. Metronidazole is a drug that is activated by the microbial proteins flavodoxin and feredoxin found in microaerophilc and anaerobic bacteria and certain protozoans. Once activated, the metronidazole puts nicks in the microbial DNA strands.
For more information on antibiotics and how they work, see the following CourseArc lesson:
Contributors and Attributions
Dr. Gary Kaiser (COMMUNITY COLLEGE OF BALTIMORE COUNTY, CATONSVILLE CAMPUS)