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.

History behind World brain Tumor day:June 8

June 8 2020 is also observed as World Brain Tumor Day apart from World Ocean Day which was intiated by a non profit organization in Germany called Deutsche Hirntumorhilfe in German.

They are providing facilities for scientists and health professionals to develop efficient treatment of Brain tumor. They also provide support to the Brain tumor patients and their families.

Apart from the tribute given, This day is also observed as international day to provide awareness about the disorder and spread information on it.

A Tumor is basically the abnormal growth of cells. This can be broadly decided into two Benign (non-cancerous) and Malignant (cancerous). Malignant tumor can be again divided into primary originating from Brain Or spine where as secondary are those cancer that spread from elsewhere in the body to the Brain. This secondary is more common than primary.

Causes and major risk factors:

The exact cause of brain cancer is unknown. However, factors that can increase your risk of brain cancer include exposure to high doses of ionizing radiation and a family history of brain cancer.

Cancer in other part of the body is also a risk factor. Major cancers that spread to Brain are:

  • Lung cancer
  • Breast cancer
  • Kidney cancer
  • Bladder cancer
  • Melanoma

Other factors are:

  • increased age
  • long-term smoking
  • exposure to pesticides, herbicides, and fertilizer
  • working with elements that can cause cancer, such as lead, plastic, rubber, petroleum, and some textiles
  • having an Epstein-Barr virus infection, or mononucleosis

Symptoms

Symptoms that arises due to increased pressure inside the skull. They are:

Severe head ache associated with nausea and vomiting, blurring or dimmed vision, excessive sleepiness, loss of memory, seizures.

Symptoms that are arise due to location of tumor. They are:

Weakiness of one side of body, hearing loss, visual blindness, facial deviation, slurring of speech.

Diagnosis method

CT scan or MRI scanning of the brain. Further diagnosis can be done by PET scan or angiography.

Treatment

Surgery is the main treatment. Modern micro surgical methods and aids such as neuro navigation and intra op imaging have made surgery safe and effective.

Other modalities such as Gamma knife/stereotaxis radiosurgery, radiation therapy and chemotherapy may be used alone or in combination

Prognosis

Brain tumor is considered as incurable disease but if given proper treatment it gives good outcome and patients are able to go to their normal lives.

Conclusion

Brain tumor can give good outcome when diagnosed and treated early. It may lead to severe mental, physical and financial burden to the patient and family. One should consult the best doctor and get adequate treatment. More public awareness need to be given to reduce panic.

ANTIBACTERIAL CHEMOTHERAPY-INTRODUCTION AND DEVELOPMENT

Antibacterial Chemotherapy refers to the use of any chemical or drug for the treatment of bacterial diseases. It is the part of antimicrobial chemotherapy.
Antimicrobial chemotherapy can be divided into several branches on the basis of type of pathogen, for e.g.
For bacterial pathogen – Antibacterial Chemotherapy
For viral pathogen – Antiviral Chemotherapy
For fungal pathogen – Antifungal Chemotherapy, etc

ANTIMICROBIAL CHEMOTHERAPY –
Chemotherapy may either mean involvement of any drug that fight against any cancerous cell or it may involve the use of any antimicrobial drug to cure diseases caused by infectious microorganisms or pathogens.
Antimicrobial drugs work by different mechanisms for different type of organisms. The overall mechanism by which any antimicrobial drug functions is by interfering with the structure and/or function of microorganisms. They either directly kill microbial cell or function by inhibiting their growth.

DEVELOPMENT OF ANTIMICROBIAL CHEMOTHERAPY
The development of chemotherapy has been known to begin with the successful research of a German physician, Paul Ehrlich (1854-1915).
Ehrlich was always fascinated to learn more about the dyes that bind to and stain the microbial cells. He was sure and stated that one of the dyes could be used as a chemical that would selectively destroy or kill the infectious pathogen inside the human body without making any harm to human cell and he named it “Magic Bullet”. Working more on this, he was able to find that the dye, trypsan red was active against the trypanosome that causes African Sleeping Sickness. Later, Ehrlich with his assistant Sahachiro Hata tested a variety of arsenic-based chemicals on Syphilis-infected rabbits and was successful in finding that Arsphenamine (an arsenic based chemical compound) was active against the Syphilis spirochete which was then made available in the market.
The other German scientist, Domagk in 1927 found the another Magic Bullet to treat diseases. He observed the antimicrobial activity of a synthetic dye, Prontosil Red which was able to cure Streptococcal and Staphylococcal infections with very limited toxicity. Sulfanilamide (one of the active breakdown products of prontosil in body) was the first synthetic antimicrobial drug.

A Synthetic Antimicrobial is a drug that is developed from any type of a chemical compound that is not found in nature.

Penicillin was the first naturally synthesized antibiotic which was initially discovered by a 21 years old French medical student. No one remembered his work until Alexander Fleming in September 1928 accidently rediscovered the antibiotic. The petri plate of Staphylococcus which was inoculated by Fleming was found to develop certain molds which made the clear zone of inhibition of staph-bacterial species around them. It was meant that the mold infected the petri plates even before the bacteria were inoculated. Fleming suggested that the mold (probably the strain of Penicillium notatum) produced a substance which inhibited the bacterial growth surrounding it and hence had an antibacterial property.
Further experiment results concluded that Penicillin was active against streptococci, meningococci and Corynebacterium diphtheriae, which is the causative agent of diphtheria.
The isolation, mass production and purification of penicillin were accomplished by Howard Florey and Ernst Chain for which they got the nobel prize. They found that the penicillin once pured was effectively able to show antimicrobial properties against streptococcal infection in mice.
Later, Dorothy Hodgkin observed and analyzed the structure of various naturally synthesized products using X-rays. Because of her observation on the chemical structure of naturally synthesized penicillin, it was easier for many scientists to produce a variety of semi synthetic penicillin.

A semisynthetic antimicrobial is defined as the chemically modified product of a natural antibiotic.

After the discovery of penicillin, other scientists got the determination for the discovery of more antibiotics by natural or chemical synthesis.
Selman Waksman developed a new antibiotic, Streptomycin which was produced by the actinomycete, Streptomyces griseus. This antibiotic was discovered by the soil microorganisms, particularly bacteria and fungi. It was the first discovery of antibiotic- producing soil microorganism. It was found that streptomycin was successful in treating tuberculosis.
Other microorganisms producing chloramphenicol, neomycin, terramycin and tetracycline were also isolated later.