ANTI-CELL WALL ANTIBACTERIAL DRUGS

Selective toxicity is the important characteristic of antimicrobial drugs which means that any drug is selective against a particular microorganism and also selectively act on a particular site. Not all drugs can act on every site. There are many sites at which any drug acts such as cell wall, cell membrane of the bacterial cell. Basically selective toxicity explains that any drug will only act on the pathogen and not on the host.
ANTI-CELL WALL DRUGS
Anti-cell drugs are those drugs which act on the cell wall of the bacterial pathogen and not the host. There are variety of drugs which fall under this category. The major class is of beta-lactam antibiotics among which penicillin is the drug which is studied the most. The drugs can be administered into the patient’s body by different ways like intramuscular, intravenous, or can be applied as topical preparations. But mostly, these drugs are intramuscular or intravenous drugs. The following points explain the further different mechanisms of anti-cell wall drugs.
There are 3 different mechanisms by which anti-cell wall drugs work and thus they are also classified as following:

  1. First classification involves the drugs that directly interact with Penicillin-Binding-Proteins (PBPs) and inhibit the transpeptidase activity which in turn inhibits the attachment of newly formed peptidoglycan subunit to the pre-existing one.
    This is the main mechanism of β-lactam antibiotics. These antibiotics include Penicillin (penams), cephalosporins, Penems, Carbapenems, and monobactams.
    These antibiotics bind to the penicillin-binding proteins which are enzymes present in the bacterial cell wall. Different β-lactam antibiotics bind in a different way. After the antibiotics bind to the enzyme, it changes the morphological response of the bacteria to the antibiotic.
  2. Second classification involves the drugs that bind to the peptidoglycan subunit, blocking different processes.
    The important class of compounds called as glycopeptides are mainly involved in this mechanism of anti-cell wall antibiotics.
    Vancomycin and Teicoplanin are the major examples of glycopeptide antibiotics.
    Vancomycin kills only gram-poitive bacteria whereas Teicoplanin is active against both. The overall mode of action of glycopeptides antibiotics is blocking transpeptidation i.e. similar to β-lactam antibiotics, they also inhibit the transpeptidase activity, and transglycosylation i.e. they being large in size attach to the peptidoglycan subunits thus creating a blockage which does not allow the cell wall subunits to attach to the growing peptidoglycan backbone.
  3. Third classification involves the drugs that block the transport of peptidoglycan subunits across cytoplasmic membrane.
    The main example of such type of drugs is bacitracin, which is a simple peptide antibiotic originally isolated from Bacillus subtilis.
    The mode of action of these class of drugs is blocking the activity of specific cell membrane lipid carriers which act as the attachment surface for peptidoglycan precursors and help in their movement from cell cytoplasm to exterior of the cell. This activity of lipid carriers is inhibited by bacitracin like drugs and they finally prevent the incoroporation of those precursors into cell wall thus inhibiting its biosynthesis.

Although, its route of administration is mostly oral or intramuscular, bacitracin is also known to show its effects when used as topical ointments like Neosporin.

MECHANISM OF DIFFERENT TYPES OF ANTIBIOTICS

Antibacterial Drugs are classified according to their site of action which are as follows :

CELL WALL SYNTHESIS INHIBITORS
There are 3 different mechanisms by which anti-cell wall drugs work and thus they are also classified as following:

  1. First classification involves the drugs that directly interact with Penicillin-Binding-Proteins (PBPs) and inhibit the transpeptidase activity which in turn inhibits the attachment of newly formed peptidoglycan subunit to the pre-existing one.
    This is the main mechanism of β-lactam antibiotics. These antibiotics include Penicillin (penams), cephalosporins, Penems, Carbapenems, and monobactams.
    These antibiotics bind to the penicillin-binding proteins which are enzymes present in the bacterial cell wall. Different β-lactam antibiotics bind in a different way. After the antibiotics bind to the enzyme, it changes the morphological response of the bacteria to the antibiotic.
  2. Second classification involves the drugs that bind to the peptidoglycan subunit, blocking different processes.
    The important class of compounds called as glycopeptides are mainly involved in this mechanism of anti-cell wall antibiotics.
    Vancomycin and Teicoplanin are the major examples of glycopeptide antibiotics.
    Vancomycin kills only gram-poitive bacteria whereas Teicoplanin is active against both. The overall mode of action of glycopeptides antibiotics is blocking transpeptidation i.e. similar to β-lactam antibiotics, they also inhibit the transpeptidase activity, and transglycosylation i.e. they being large in size attach to the peptidoglycan subunits thus creating a blockage which does not allow the cell wall subunits to attach to the growing peptidoglycan backbone.
  3. Third classification involves the drugs that block the transport of peptidoglycan subunits across cytoplasmic membrane.
    The main example of such type of drugs is bacitracin, which is a simple peptide antibiotic originally isolated from Bacillus subtilis.
    The mode of action of these class of drugs is blocking the activity of specific cell membrane lipid carriers which act as the attachment surface for peptidoglycan precursors and help in their movement from cell cytoplasm to exterior of the cell. This activity of lipid carriers is inhibited by bacitracin like drugs and they finally prevent the incoroporation of those precursors into cell wall thus inhibiting its biosynthesis.

Although, its route of administration is mostly oral or intramuscular, bacitracin is also known to show its effects when used as topical ointments like Neosporin.

INHIBITORS OF PROTEIN SYNTHESIS
Protein Inhibitors can be divided into 2 parts:

  1. Inhibitors binding to 30S subunits
    • Aminoglycosides bind to the bacterial ribosome, after which they cause tRNA mismatching and thus protein mistranslation.
    This occurs by mismatching between codons and anticodons, which synthesize proteins with incorrect amino acid. This mistranslated protein, along with correctly translated proteins move into move into the periplasm where most of the mistranslated proteins are degraded and some of them are inserted into cytoplasmic membrane. This causes disruption of the membrane, ultimately killing the bacterial cells.
    • Tetracyclines are bacteriostatic and block the binding of tRNAs with the ribosome during translation thus inhibiting protein synthesis. Most of the tetracycline class of drugs are broad spectrum and are active against wide range of bacteria.
  2. Inhibitors binding to the 50S subunit
    • Macrolides are the large class of naturally produced secondary antibiotics. They are basically broad spectrum, bacteriostatic antibiotics. Their main mode of action is blocking peptide chain elongation and they inhibit the formation of peptide bond.
    Patients allergic to penicillins are recommended erythromycin which is a macrolide.
    • Lincosamides include lincomycin and clindamycin. Though they are structurally different but functionally similar to macrolides. They are specifically known to inhibit streptococcal and staphylococcal infections.
    • Chloramphenicol also inhibits peptidyl transferase reaction inhibiting peptide bond formation. It was the first broad spectrum antibiotic and is very much active against a broad range of bacterial pathogens but is very toxic and can cause side.

INHIBITORS OF MEMBRANE FUNCTION
Biological cytoplasmic membranes are basically composed of lipids, proteins and lipoproteins. The cytoplasmic membrane acts as a selective barrier which allows the transport of materials between inside the cell and the environment.
A number of antibacterial agents work by targeting the bacterial cell membrane. They basically are involved in the disorganization of the membrane. Polymyxins and Lipopeptides are the main anti- cell membrane agents.

NUCLEIC ACID SYNTHESIS INHIBITORS
These drugs inhibit nucleic acid synthesis function by either of the following:

  1. Interfere with RNA of bacterial cell
    Antibacterial drugs of this mechanism are selective against bacterial pathogenic cells.
    For example: The drug rifampin, belonging to the drug class rifamycin blocks the bacterial RNA polymerase activity. It is also active against Mycobacterium tuberculosis and thus id used in the treatment of tuberculosis infection. It also shows side effects.
  2. Interfere with DNA of bacterial cell
    There are some antibacterial agents that interfere with the activity of DNA gyrase.
    The drug class fluoroquinolones show this mechanism. They are borad spectrum antibacterial agents. Some examples of drugs in fluoroquinolone family are Ciprofloxacin, Ofloxacin, Moxifloxacin, etc

INHIBITORS OF METABOLIC PATHWAYS
There are some antibacterial drugs which act as ANTIMETABOLITES and inhibits the metabolic pathways of bacteria.
• The sulfonamides block the production of dihydrofolic acid.
This blocks the production of purines and pyrimidines required for nucleic acid synthesis by blocking the biosynthesis of folic acid. Their mechanism of action is bacteriostatic and they are broad spectrum antibacterial agents. Though humans also obtain folic acid but these drugs are selective against bacteria.
Sulfones are also structurally and functionally similar to sulfonamides.
• Trimethoprim is used in the same folic acid synthesis pathway but at a different phase, in the production of tetrahydrofolic acid.
• There is another drug, Isoniazid which is an antimetabolite only selective against mycobacteria. It can also be used to treat tuberculosis when used in combination with rifampin and streptomycin.

INHIBITORS OF ATP SYNTHASE
There is a class of drug compounds called as Diarylquinolones that are specifically active against mycobacterial growth. They block the oxidative phosphorylation process and finally leading to reduced ATP production which either kill or inhibit the growth of mycobacterial species.

HOW TO CHOOSE MOST APPROPRIATE ANTIBACTERIAL CHEMOTHERAPY?

Choosing an antibacterial drug therapy can depend on various factors which are mentioned below:

BACTERIOSTATIC V/S BACTERICIDAL
Antibacterial chemotherapeutic agents can be categorized as bacteriostatic and bactericidal on the basis of their interaction with the targeted bacterial pathogens.
Bacteriostatic drugs work by inhibiting the growth of specific bacteria. Static drugs work by reversibly inhibiting the growth i.e. if the agent (drug) is removed or if its effect if over, the microorganism will get recovered and will grow again causing the same infection again.
Bactericidal drugs work by directly killing the target bacteria from the location. Cidal drugs may act as static drugs at low concenteration.

Use of any drug also depends on the immune system of the host because static drug does not completely eliminate the target bacteria. For patients with strong immune system, either static or cidal drugs can be used for curing infection while in case of immunocompromised individual, only cidal drugs are essentially required for complete removal of the bacterial infections.

SPECTRUM OF ACTIVITY
On the basis of their range or spectrum of activity, the chemotherapeutic agents can be broadly categorized into 5 different categories:

  1. Narrow spectrum antibiotics are only active against less no. of microorganisms. They target only a specific strains of bacterial pathogens, especially gram positive bacteria.
  2. Moderate spectrum antibiotics target most of the gram positive bacterial pathogens as well as most systemic, enteric and urinary tract gram negative bacterial pathogens.
  3. Narrow and moderate spectrum antibiotics are known to cover all the β-lactam antibiotics which can effectively work against gram positive and negative bacteria. Some members of this classification are only effective against gram negative while others can also kill gram positive bacteria.
  4. Broad spectrum antibiotics, as the name suggests targets a broad range of bacterial pathogens which includes almost all the prokaryotic organisms except mycobacteria and pseudomonas. They are also effective against polymicrobic infections (mixed infections caused by multiple bacterial species). It is used when other spectrum antibiotics fail to treat infections due to drug resistance. There is a risk of superinfection while using broad spectrum antibiotics.
  5. Anti-mycobacterial antibiotics are only effective against mycobacterial strains of pathogenic bacteria.

DOSAGE AND ROUTE OF ADMINISTRATION
• Dosage –
The minimum or maximum amount of drug that a patient is given is the dosage of the drug. The dosage of the particular drug needs to be determined carefully to ensure that the optimum level of that particular drug is achieved at the site of infection for the elimination of the infection without causing any toxic side effects. Therefore, the selection and standardization of dosage of a particular drug is done so that it has the minimum side effect.
• Route of administration –
It can be defined as the method by which a drug is introduced in the patient’s body. There are different ways of administration of a drug. The most preferred drugs are the one that can be administered orally because it is easier for the patients to take them even at their home without visiting the health care professionals again and again. However, it is observed that not all drugs can be absorbed from the gastro intestinal tract. E.g. Bacitracin, Polymyxin and many antifungals. These drugs may be available to the patients in the form of topical preparations so that they can be applied for the treatment of superficial skin infections.
The another condition arises when a patient is unable to take oral drug initially due to some illness like vomiting. In that condition, the drug is preferably administered through parenteral route i.e. intramuscular or intravenous injections. In general, for most of the drugs, the drug levels in plasma introduced via intravenous is higher than that of oral or intramuscular route.

POTENTIAL FOR SIDE EFFECTS
The adverse effects which are seen in the patient’s body after administration of any drug can be classified into 3 main types:

  1. PHARMACOLOGICAL SIDE EFFECTS
    These are the toxic side effects which the drug shows by damaging the infected or even healthy cells by the production of some toxic chemicals on cell surface or their interior.
  2. ALLERGIC SIDE EFFECTS
    Some drugs show the allergic reactions in the patient’s body which is due to the antigen-antibody reaction which in turn effects other cells and show some allergy.
  3. BIOLOGICAL TYPE SIDE EFFECTS
    This type of side effect is worst and it involves interference of the drug with the normal microflora of the body which is followed by either local chemical damage or superinfection.

POTENTIAL INTERACTION BETWEEN DRUGS
Most of the time, antibiotics are administered in the patient’s body as a single agent but many time it becomes necessary to take two or more drugs at a time. So, different drugs administered at a single time show some interaction among them.
The interaction may be positive or negative.
Sometimes, a synergistic or positive interaction is shown by two antibiotics when they are administered together. Some drugs show bactiostatic effect when used as a single agent but are able to show bactericidal effect when combined with other antibiotic.
On the other hand, some drugs when used together show negative effect or antagonistic effect. Antagonism can occur between two antimicrobial or between one antimicrobial and one non-antimicrobial. The antagonistic interactions thus cause toxic side effects, loss of drug activity, decreased effect of drug at the site of infection. For e.g. Penicillin and bacteriostatic drugs are antagonists of each other.