Classification Of Antibiotics

Definition

The original definition of antibiotics was material derived from microorganisms that suppress growth and sometimes kill the microorganism. Synthetic material was added later, when they were able to make synthetic antibiotics.


Classification

1. Bactericidal drugs kill the target bacterium or fungus and are more effective. You would use these types of drugs to treat endocarditis, meningitis, osteomyelitis, and other invasive bacterial infections. Hosts with low immune systems should also be treated with bactericidal drugs. These drugs include β- Lactams, aminoglycosides, and fluoroquinolones.
2. Bacteriostatic drugs inhibit growth and can be helpful cuz they let the normal host defenses to destroy the microorganisms. You would use these to treat infections such as cystitis. These drugs include tetracycline, sulfonamides, clindamycin, and chloramphenicol. Some organisms require 2 agents for killing such as entercocci.

We can classify antibiotics by their mode of action.

1. Cell Wall Inhibitors: These include the Glycopeptides (ex vancomycin), Bacitracin, Cycloserin, Fosfomycin, and the β–lactams (penicillins, cephalosporines, monobactams, carbapenems) that are important to know because if someone is allergic to penicillin you can’t give them a different β-lactam.

Antibiotic agents usually diffuse easily through Gram +ve cell walls, but in Gram –ve they need to go through narrow walls and it’s harder. Peptidoglycan is the critical attack site in cell wall inhibition because it is not found in eukaryotes, and it’s loss = cell death. It is a cross-linked complex of polysaccharides and peptides, which has been discussed, in earlier lectures (see bacteriology). The cross linked structure is the reason for it’s great strength. It is synthesized in 3 stages:

Precursor formation UDP-NAM-pentapeptide and UDP-NAG are synthesized in the cytosol {inhibitors here = fosfomycin and cycloserine – this is not used because it is also toxic to the nervous system)

Polymer formation precursor molecules are transferred to phosphorylated undecaprenyl alcohol (a lipid carrier in the cytoplasmic membrane) and are transported to the outside surface. Bacitracin interacts with the carrier and so prevents precursor transport.Transglycosylases and transpeptidases reticulate the peptidoglycan units. β–lactams inactivate transpeptidases because they bind them so D-ala-D-ala can’t. Glycopeptides inhibit both transglycosylases and transpeptidases by binding to the D-ala-D-ala termini, preventing anything else from binding there.

Cross Linkinglinking the new peptidoglycan strand into the existing molecule. These enzymes are called Penicillin –Binding Proteins (PBP) because they were discovered by labeling with radioactive penicillin G. They are membrane bound and structurally resemble serine proteases. Bacteria make 4 types of PBP numbered according to molecular weight; letters are used to differentiate PBPs of similar weight (so you can PBP 2a, PBP 2b etc.)

PBPs differ in affinities for β–lactams, amounts and function in cell walls, and enzymes are different in Gram + vs. Gram – vs. anaerobic bacteria. Which PBP a β–lactam binds to affects how the bacteria will look, for example binding to PBP 3 causes bacteria to grow into long filaments and die, while binding to PBP 1 results in bulgeing and bursting of the cell wall. With PBP’s inhibited, the autolysins are unopposed which can also contribute to the antibacterial effect. β–lactamases are PBPs that inactivate the drug by catalyzing hydrolyses of the β–lactam ring.

2. 
   
   Cell Membrane Inhibitors : These cause disorganization of the membrane. Antibacterials – polymyxin, Antifungals – Polyenes (amphotericin), Imidazoles (fluconazole , itraconazole , and vorconazole). We can divide these into cationic, anionic, and neutral agents.
   1. 
      
      Polymyxin B and colistin (polymyxin E) : these are low molecular weight octapeptides that inhibit Gram – ve bacteria with –vely charged lipids on the surface. Allow nucleic acid and cations to leak out of the cell so the cell dies. Can’t be used systemically because they are toxic to the kidney and nervous system (except in cases of extreme need), but are used topically.
      
      
   2. 
      
      Polyene antibiotics  fungal membranes have sterols while bacterial membranes don’t. Polyene antibiotics bind to the sterols and make a pore in the membrane and the contents leak out. This does not work in prokaryotes.
      
      
   3. 
      
      Imidazoles : inhibit ergosterol synthesis.
      
      
   
   

3. 
   
   Nucleic Acid Synthesis Inhibitors
   1. 
      
      Inhibitors of DNA replication: Quinolones and Nitroimidazoles. Fluoroquinolones block the action of DNA gyrase and DNA topoisomerase IV that control and modify the topological states of DNA in cells. They do this by relieving supercoils, which can form during the unwinding of DNA for replication or transcription. Positive supercoils are when the front segment of DNA crosses over the back from left to right. There are a few types of topoisomerases:
      1. 
         
         Type 1: makes transient single stranded breaks in DNA and removes supercoils one at a time. In eukaryotes both topo 1 and 2 can remove both + and – supercoils. In bacteria topo 1 can only remove – supercoils.
         
         
      2. 
         
         Type 2: makes transient double stranded breaks and removes supercoils 2 at a time, and is more efficient but requires energy from ATP hydrolysis. Bacterial topo II is also called DNA gyrase and has 2 functions (a) to remove +ve supercoils during DNA replication, and, (b) to introduce –ve supercoils so the DNA molecule can be packed into the cell. It is made of two A and two B subunits. Bacterial Topo IV can only relax supercoils, it can’t make supercoils. Topo IV has 2 subunits, ParC and ParE.
         
         
      
      
   
   

2. 
   
   Inhibitors of RNA polymerase  Rifamycins. Rifampin binds to a β-subunit of RNA polymerases and prevents initiation of DNA transcription. Mammalian mitochondrial RNA synthesis is not impaired significantly.
   
   
3. 
   
   Inhibitors of nucleotide metabolism  Acyclovir  inhibits viruses by being converted to a tiphosphate and inhibiting the thymidine kinase and DNA polymerase of the herpes viruses, AZT (viruses)  inhibits the incorporation of DATP into DNA, Flucytosine (fungi)  inhibits yeast by being converted to 5-fluorouracil which inhibits thymidylate synthetase so there are not enough thymine nucleotides to replicate DNA.
   
   

4. 
   
   Protein Synthesis Inhibitors  I am sure you all know the steps of protein synthesis so I won’t go into the long explanation she gave. Instead I’ll just name the steps  formation of the initiation complex  elongation of the polypeptide chain  termination.
   1. 
      
      Inhibitors of 30S subunit  Aminoglycosides  bind to specific ribosomal proteins and to a major deep grove in the rRNA. Streptomycin was the first studied and it has a different mechanism from other aminoglycosides. It binds to the S12 protein and causes the ribosome to misread the genetic code. Others also bind the L6 protein of the 50S ribosome. Eukaryotes are relatively unaffected but ribosomes in the mitochondria are sensitive to their effects.
      
      
   
   

2. 
   
   Inhibitors of 50S subunit 
   1. 
      
      Macrolides, Ketolides, Lincinoids  have large lactone rings, bind to the peptidyl side of the 50S subunit. Impair peptidyltransferase and interferes with the translocation of the peptide chain from A to P site, and promotes dissociation of peptidyl-tRNA from the ribosomes.
      
      
   2. 
      
      Chloramphenicol  bacteriostatic, binds to a peptidyltransferase enzyme on the 50S ribosome.
      
      
   3. 
      
      Fusidic acid
      
      
   4. 
      
      Streptogramin  relatives of macrolides, binds to 50S
      
      
   5. 
      
      Oxazolidinones  binds to 50S near the 30S interface which prevents the 30S initiation complex from forming the 70S complex, blocking initiation of protein synthesis. Bacteriostatic
      
      
   
   

5. 
   
   Metabolic Inhibitors  Folate inhibitors  bacteria make folic acid while humans take it in from their diet. Sulfonamides and trimethoprim block the biosynthesis of tetrahydrofolate, which is a carrier of 1C fragments and is necessary for DNA, RNA, and cell wall synthesis.
   
   

Category: Pharmacology Notes