II. THE PROKARYOTIC CELL: BACTERIA
D. CONTROL OF BACTERIA
1. How Control Agents Affect Bacterial Structures and Functions
The basis of chemotherapeutic control of bacteria is selective toxicity (def). Selective toxicity means that the chemical being used should inhibit or kill the intended pathogen without seriously harming the host. A broad spectrum agent (def) is one generally effective against a variety of gram-positive and gram-negative bacteria; a narrow spectrum agent (def) generally works against just gram-positives, gram-negatives, or only a few bacteria. Such agents may be cidal or static in their action. A cidal (def) agent kills the organism while a static (def) agent inhibits the organism's growth long enough for body defenses to remove it. There are two categories of antimicrobial chemotherapeutic agents: antibiotics and synthetic drugs. Antibiotics (def) are metabolic products of one microorganism that inhibit or kill other microorganisms. Synthetic drugs (def) are antimicrobial drugs synthesized by chemical procedures in the laboratory. Many of today's antibiotics are now actually semisynthetic and some are even made synthetically.
We will now look at the two sides of the story with regards to controlling bacteria by means of chemicals:
1. How Control Agents May Affect Bacterial Structures or Functions
2. How Bacteria May Resist Our Control Agents
We will now look at the various ways in which our control agents affect bacteria altering their structures or interfering with their cellular functions.
1. How Control Agents May Affect Bacterial Structures or Functions (see Fig. 1)
a. Many antibiotics inhibit normal synthesis of peptidoglycan (def) by bacteria and cause osmotic lysis.
In order for bacteria to increase their size following binary fission, enzymes called autolysins break the cross links in the peptidoglycan (see Fig. 2) while transpeptidase enzymes add new peptidoglycan monomers and reseal the wall. Interference with this process results in a weak cell wall and lysis of the bacterium. Examples include the penicillins (penicillin G, methicillin, oxacillin, ampicillin, amoxicillin, ticarcillin, etc.), the cephalosporins (cephalothin, cefazolin, cefoxitin, cefotaxime, cefaclor, cefoperazone, cefixime, ceftriaxone, cefuroxime, etc.), the carbapenems (imipenem, metropenem), the monobactems (aztreonem), the carbacephems (loracarbef), and the glycopeptides (vancomycin, teichoplanin).
1. For example, penicillins and cephalosporins bind to the transpeptidase enzymes (also called penicillin-binding proteins) responsible for resealing the cell wall as new peptidoglycan monomers are added during bacterial cell growth. This blocks the transpeptidase enzymes from cross-linking the sugar chains and results in a weak cell wall and subsequent osmotic lysis of the bacterium.
2. Glycopeptides like vancomycin, on the other hand, bind directly to the cell wall peptides and block the transpeptidase enzymes from cross-linking the sugar chains. Vancomycin also appears to block transglycolation, the bonding of the NAMs to the NAGs. This results in a weak cell wall and subsequent osmotic lysis of the bacterium.
To view a Quick Time video of penicillin killing a bacterium, see the CELL'S ALIVE web page. To view articles on penicillin and antibiotics, see J.Brown's Bugs in the News web page ay the University of Kansas.
b. INH (isoniazid) block the incorporation of mycolic acid into acid-fast cell walls (see Fig. 3) while ethambutol interferes with the synthesis of other cell wall components thus inhibiting cell wall synthesis.
c. A very few antibiotics (polymyxins, tyrocidins) and many disinfectants (def) and antiseptics (def) (orthophenylphenol, chlorhexidine, hexachlorophene, zephiran, alcohol, etc.) used during disinfection (def) alter the cytoplasmic membrane (def) causing leakage of cellular needs (see Fig. 1).
d. Some antimicrobials inhibit normal nucleic acid replication in bacteria (see Fig. 1).
1. The fluoroquinolones (norfloxacin, lomefloxacin, fleroxacin, ciprofloxacin, enoxacin, trovafloxacin, gatifloxacin, etc.) work by inhibiting one or more of a group of enzymes called topoisomerase (def), enzymes needed for bacterial nucleic acid synthesis. For example, DNA gyrase (topoisomerase II), mentioned earlier in this unit, breaks and rejoins the strands of bacterial DNA to relieve the stress of the unwinding of DNA that occurs during DNA replication and transcription (def).
2. The sulfonamides and trimethoprim (co-trimoxazole - a combination of sulfamethoxazole and trimethoprim, sulfanilamide, etc.) 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 (see Fig. 4). This is done through a process called competitive antagonism whereby a drug chemically resembles a substrate in a metabolic pathway. Because of their similarity, either the drug or the substrate can bind to the substrate's enzyme. While the enzyme is bound to the drug, it is unable to bind to its natural substrate and that blocks that step in the metabolic pathway. Sulfonamides such as sulfamethoxazole tie up the first enzyme in the pathway, the conversion of para-aminobenzoic acid to dihydropteroic acid. Trimethoprim binds to the third enzyme in the pathway, an enzyme that is responsible for converting dihydrofolic acid to tetrahydrofolic acid. Without the tetrahydrofolic acid, the bacteria cannot synthesize DNA or RNA.
3. 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.
e. Rifampin blocks transcription (def) by inhibiting bacterial RNA polymerase, the enzyme responsible for transcription of DNA to mRNA.
f. Many antibiotics alter bacterial ribosomes (def), interfering with translation (def) and thereby causing faulty protein synthesis (see Fig. 1). To learn more detail about the specific steps involved in translation during bacterial protein synthesis, see the animation that follows. Protein synthesis will be discussed in greater detail in Unit 6.
1. The aminoglycosides (streptomycin, neomycin, netilmicin, tobramycin, gentamicin, amikacin, etc.) bind irreversibly to the 30S subunit of bacterial ribosomes and prevent the 50S ribosomal subunit from attaching to the translation initiation complex. By binding to the 30S subunit, the subunit to which mRNA attaches, aminoglycosides also cause the misreading of the codons (see Fig. 5) resulting in tRNA inserting the wrong amino acids into the protein.
2. The tetracyclines (tetracycline, doxycycline, demeclocycline, minocycline, etc.) bind reversibly to the 30S subunit, distorting it in such a way that the anticodons of charged tRNAs (def) cannot align properly with the codons of the mRNA (def).
3. The macrolides (erythromycin, azithromycin, clarithromycin, dirithromycin, troleandomycin, etc.) bind reversibly to the 50S subunit.They inhibit elongation of the protein by the enzyme peptidyltransferase that forms peptide bonds between the amino acids, by preventing the ribosome from translocating down the mRNA (def), or both.
4. The oxazolidinones (linezolid) bind to the 50S ribosomal subunit appear to interfere with the initiation of translation (def).
5. The streptogramins (a combination of quinupristin and dalfopristin) bind to different sites on the 50S ribosomal subunit and work synergistically to inhibit translocation.
g. Many disinfectants (chlorine, iodine, iodophores, mercurials, silver nitrate, formaldehyde, ethylene oxide, etc.) inactivate bacterial enzymes and thus block metabolism.
For a more detailed description of any specific antimicrobial agent, see the website of RxList - The Internet Drug Index.
|
For further
information on the modes of action of antibiotics, see:
|
Doc
Kaiser's Microbiology Home Page
Copyright © Gary E. Kaiser
All Rights Reserved
Updated: Nov. 28, 2001
Please send comments and inquiries
to Dr.
Gary Kaiser