Antibiotics and chemotherapeutic agents

PHRM 304

Antimicrobials are drugs used to treat infection. They may be:

Antibacterial
Antibacterials are microbial metabolites or synthetic analogs inspired by them that, in small doses, inhibit the growth and survival of bacteria without serious toxicity to the host.

Antiviral Antifungal Antiprotozoal Anthelmintic

 Antibiotics natural substances produced by microorganisms: penicillins, tetracyclines. Semi-synthetic antibiotics chemically modified natural products: amoxicillin, doxycycline. Synthetic antibacterial agents chemically synthesized, unrelated to natural substances: sulfisoxazole, ciprofloxacin. Chemotherapeutic agents refer to chemicals that kill cells, specifically those of micro-organisms or cancer. Antibacterial agents may either kill the microorganism (bactericidal) or may retard their growth (bacteriostatic) so that the bodys own immune system can overcome the infection.

Semisynthetic

Amoxycillin
Natural

Benzylpenicillin, commonly known as penicillin G (PEN G)

The bacterial cell

The success of antibacterial agents owes much to the fact that they can act selectively against bacterial cells rather than animal cells. This is largely due to the fact that bacterial cells and animal cells differ both in their structure and in the biosynthetic pathways which proceed inside them. 1. The bacterial cell has a cell wall, as well as a cell membrane, whereas the animal cell has only a cell membrane. The cell wall is crucial to the bacterial cell's survival.

Bacteria have to survive a wide range of environments and osmotic pressures, whereas animal cells do not. If a bacterial cell lacking a cell wall was placed in an aqueous environment containing a low concentration of salts, water would freely enter the cell due to osmotic pressure. This would cause the cell to swell and eventually 'burst'. The cell wall does not stop water flowing into the cell directly, but it does prevent the cell from swelling and so indirectly prevents water entering the cell.

Fig. The bacterial cell

2. The bacterial cell does not have a defined nucleus, whereas the animal cell does. 3. Animal cells contain a variety of structures called organelles (e.g. mitochondria, etc.), whereas the bacterial cell is relatively simple. 4. The biochemistry of a bacterial cell differs significantly from that of an animal cell. For example, bacteria may have to synthesize essential vitamins which animal cells can acquire intact from food. The bacterial cells must have the enzymes to catalyze these reactions. Animal cells do not, since the reactions are not required.

Mechanism of action
Folic acid metabolism:
Para-aminobenzoic acid (PABA)
[GTP]

+ Pteridine

Dihydropteroate synthetase

Dihydropteroic acid
L-Glutamate Dihydrofolate synthetase

Dihydrofolic acid (folic acid)

2 NADPH 2 NADP+ Dihydrofolate reductase

Tetrahydrofolic acid Purines DNA, RNA

Cofactors

Thymidine DNA

Methionine t RNA, Proteins

Mechanisms of antibacterial action

There are five main mechanisms by which antibacterial agents act Inhibition of cell metabolism: Antibacterial agents which inhibit cell metabolism are called antimetabolites. These compounds inhibit the metabolism of a microorganism, but not the metabolism of the host. They do this by inhibiting an enzyme-catalyzed reaction which is present in the bacterial cell, but not in animal cells. The best known examples of antibacterial agents acting in this way are the sulfonamides.

Fig. Sites of antibacterial action

 Inhibition of bacterial cell wall synthesis: Inhibition of cell wall synthesis leads to bacterial cell lysis (bursting) and death. Since animal cells do not have a cell wall, they are unaffected by such agents. Agents operating in this way include penicillins and cephalosporins. Interactions with the plasma membrane: Some antibacterial agents interact with the plasma membrane of bacterial cells to affect membrane permeability. This has fatal results for the cell. Polymyxins and tyrothricin operate in this way.

Polymyxins disrupt the structure of the bacterial cell membrane by interacting with its phospholipids.

Inhibition of nucleic acid transcription and replication: Inhibition of nucleic acid (DNA, RNA) function prevents cell division and/or the synthesis of essential enzymes. Agents acting in this way include nalidixic acid and proflavine.

 Disruption of protein synthesis: Disruption of protein synthesis means that essential enzymes required for the cell's survival can no longer be made. Agents which disrupt protein synthesis include the rifamycins, aminoglycosides, tetracyclines, and chloramphenicol. In short the antibiotic targets are- Inhibition of cell metabolism - Inhibition of bacterial cell wall synthesis - Interactions with the cell membrane - Disruption of protein synthesis - Inhibition of DNA and RNA synthesis

What are the probable mechanisms by which some bacteria acquire resistance against antibiotics?
The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are: 1. Drug inactivation or modification: e.g. enzymatic deactivation of Penicillin G in some penicillin-resistant bacteria through the production of -lactamases. 2. Alteration of target site: e.g. alteration of PBP (Penicillin-binding proteins ) the binding target site of penicillins- in MRSA (multiple-resistant Staphylococcus aureus) and other penicillin-resistant bacteria.

3. Alteration of metabolic pathway: e.g. some sulfonamide-resistant bacteria do not require paraaminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides. Instead, like mammalian cells, they turn to utilizing preformed folic acid. - Resistant bacteria may produce high level of PABA. 4. Reduced drug accumulation: by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell surface.