M4s1: Antibiotics, Antifungal, Antiviral Agents

Question 1

What is an antibiotic

Answer 1

-chemical substance that suppresses the growth of bacteria and may eventually destroy them
*anitbiotics refer specifically to chemical substance produced by microorganisms but in this course will also refer to non-synthetic compounds
-purpose of antibiotics to stop bacterial infection
-accomplished through bacteriostatic or bactericidal effects

Question 2

Bacteriostatic

Answer 2

-inhibits growth and reproduction of bacteria

Question 3

Bactericidal

Answer 3

-directly kills the bacteria

Question 4

Structure of bacterial cells

Answer 4

-rigid outer layer = cell wall which completely surrounds the cytoplasmic membrane
-cell wall contains peptidoglycan layer, which is a complex, cross-linked polymer of polysaccharides and polypeptides
-cross-links give cell wall its structural rigidity and responsible for maintaining cell’s shape and integrity and preventing cell lysis from high osmotic pressure
*refer to goodnotes for image

Question 5

Cell lysis

Answer 5

-cell membrane breaking down

Question 6

Gram-Positive vs Gram-negative bacteria

Answer 6

-based on composition of the cell wall
*refer to goodnotes for image and more info

Question 7

Classification of antibiotics by spectrum

Answer 7

-classified 2 ways
1. Spectrum of microorganisms affected
Narrow spectrum antibiotics: useful against particular species of microorganisms. Ex. Penicillin G primary effective against Gram-positive bacteria
Broad spectrum antibiotics: effective against wider range of microorganisms, including both Gram-positive and Gram-negative bacteria. Ex. Tetracyclines

2. By biochemical pathway (targeted in the bacterial cell)
   -antibiotics utilize concept of selective toxicity by targeting and interfering with essential components of biochemical reactions in bacteria, killing the bacteria
   -classifying antibiotics this way allows for discussion of antibiotics with similar mechanisms of actions
   Cell Wall Synthesis inhibitors: function to stop proper formation of bacterial cell wall and/or membrane, influencing the structural integrity of cell (2 classes learning about: penicillins and cephalosporins)
   DNA synthesis inhibitors: inhibit DNA replication in bacteria, preventing bacterial growth (fluroquinolones)
   Protein synthesis inhibitors: inhibit protein translation within bacteria and thereby protein synthesis (tetracyclines and marcolides)
   Metabolic inhibitors: block the formation of key metabolic substrates needed for bacteria to survive and reproduce (antifolate drugs)

*refer to goodnotes image

Question 8

Cell wall synthesis: penicillins

Answer 8

-Alexander Fleming in 1929 found that penicillium mould could produce and excrete an antibacterial substance
-wasn’t successfully isolated from the mould until Second World War (1939-1945) by Florey and chain
2 types: natural (ex. Penicillin G) and semisynthetic (ex. Modified versions of penicillin G)
Natural and semisynthetic types:

Penicillin G- extracted and purified from penicillium mould, narrow spectrum that destroys mainly Gram-positive bacteria. Useful in treatment of pneumonia, middle ear infections, skin infections, and meningitis (inflammation of covering of brain and spinal cord), treatment for syphilis (other natural penicillins exist however not used clinically)

Methicillin - organisms can produce penicillinase (enzyme that breaks down penicillin) and become resistant to penicillin G. Methicillin is an antibiotic resistant to attack by penicillinase

Ampicillin and amoxicillin - antibiotics with broader spectrum compared to penicillin G. Useful against range of infections caused by Gram-negative bacteria (ex. Urinary tract infections)

Amoxicillin and cavulanic acid - combination of a semisynthetic penicillin plus an inhibitor of penicillinase that introduced into therapy to combat penicillinase-producing strains of bacteria

Question 9

Mechanism of action of penicillin

Answer 9

-penicillin closely related to D-Alanyl-D-alanine, a chemical component necessary for formation of new bacterial cell walls
-as result, penicillin interferes with a new bacterial cell wall formation and the resulting cells are formed without cell walls
-cells known as protoplasts and fragile and can readily burst
-human cells do not have cell walls and therefore unaffected by penicillin, so penicillin selectively toxic to bacteria
*refer to goodnotes for image

Question 10

Adverse effects of penicillin.

Answer 10

-most common: gastrointestinal distress (nausea and diarrhea) due to disturbance of healthy gut flora
- allergies - 1-10% of population allergic to penicillin
-if individual is allergic to one penicillin preparation, they will be allergic to all
Common allergy symptoms: rash, fever, face and tongue swelling, and itchy hives
-in rare cases: individuals experince severe difficulty breathing and marked fall in blood pressure (ex. Anaphylactic shock)

Question 11

Cell wall synthesis inhibitor: cephalosporins

Answer 11

-a second class of antibiotics that selectively inhibits cell wall synthesis
-chemically similar to penicillins but in general more resistant to penicillinase than penicillin group
-divided into 5 generations, depending on spectrum of activity mainly

Question 12

Adverse effects of cephalosporins

Answer 12

-similar to penicillins
-common include gastrointestinal side effects like nausea and diarrhea
-potential for person who is allergic to penicillin to also be allergic to cephalosporins, however that’s uncommon

Question 13

Mechanism of action of penicillin and cephalosporins (cell wall synthesis)

Answer 13

*refer to goodnotes

Question 14

Why is penicillin and cephalosporin not toxic in human cells?

Answer 14

• as human cells do not have cell walls. But rather cell ranes

Question 15

DNA synthesis inhibitors: Fluroquinolones

Answer 15

-chemically distinct class of antibiotics that inhibit bacterial DNA synthesis
Ex of this type of class of synthetic antibiotics = cirpofloxacin which can be used for oral or intravenous therapy of infections caused by wide variety of Gram-positive and Gram-negative microorganisms

Question 16

Protein Synthesis Inhibitors: Tetracyclines

Answer 16

-one of the first broad spectrum antibiotics developed
-because of widespread use for many years, many bacteria which were formerly susceptible to their action became resistant

Mechanism of action
-tetracyclines bind to 30S subunit of the mRNA-ribosome complex and prevent the addition of amino acids to the protein chain, inhibiting protein synthesis

Adverse effects
-gastrointestinal effects like nausea, vomiting, and diarrhea, discolouration of teeth, diminished bone growth

Use in special populations
-have strong affinity for calcium, therefore not used during pregnancy in children under 12

Storage
-can deteriorate into toxic degradation products if stored for long periods of time so discard outdated supplies

Question 17

Protein synthesis inhibitors: macrolides

Answer 17

-active against several bacterial infections caused by Gram-positive microorganisms
-when individual allergic to penicillin, macrolide may be an effective alternative
-erythromycin, a type of macrolide, also effective in treating infections caused by some Gram-negative bacteria
-macrolides bind to the 50S ribosomal subunit on tRNA and block peptide bond formation
Adverse effects: nausea, vomiting, and diarrhea (most common cause of discontinuing treatment with erythromycin)
*refer to goodnotes for image

Question 18

Mechanism of action of tetracycline and macrolides (protein synthesis inhibitors)

Answer 18

*refer to goodnotes for image and explanation

Question 19

Metabolic inhibitors

Answer 19

-antifolates are inhibitors of folate metabolism in bacteria
-tetrahydrofolic acid, a folate, is essential for bacteria to synthesize DNA and protein
-if tetrahydrofolic acid not formed, bacteria growth will slow
-sulfonamides and trimethoprim are both classified as antifolate drugs
*refer to goodnotes

Question 20

Combination antifolates from metabolic inhibitors

Answer 20

-by inhibiting sequential steps in metabolic pathway, a synergistic antibacterial effect is produced
-as such, a combination product containing sulfamethozazole and trimethoprim was developed
-sulfamethoxazole-trimethoprim, also known as co-trimoxazole is useful in treatment of urinary tract infections, respiratory tract infections and GI tract infections

Question 21

Antibiotic combinations

Answer 21

-some antibiotics used in combination

Use of antibiotics in combination
-therapy of severe infection where microorganism responsible is not known or the infection is so dangerous that one cannot wait to determine by laboratory tests which microorganism is responsible
-treatment of a mixed bacterial infection where no single antibiotic could eliminate all the different bacteria responsible for infection
-treating tuberculosis, where emergence of resistant mycobacterium is important hazard. Therefore, treatment is always carried out with a combination of anti tubercular drugs to decrease the chance of emergence of resistant tubercle bacilli
-infections treated by 2 antibiotics that act synergistically

Disadvantages
-unnecessary additional cost if a single antibiotic effective
-increased chance of encountering toxicity
-enchanced opportunity for resistant bacteria to arise when the combination of antibiotics being used not effective for the particular bacterial infection
-decreased number of normal populations of different bacteria, removing their inhibitory influence on potentially dangerous bacteria

Question 22

Types of antibiotics review

Answer 22

*refer to goodnotes image

Question 23

Antimicrobials

Answer 23

-an agent that kills or inhibits the growth of microbes
-include antibiotics, antifungals, antivirals, and antiparasitics

Question 24

Antimicrobial resistance

Answer 24

-emergence of resistant strains is a long standing problem with antimicrobials
-during replication, bacteria can mutate and evolve to have different properties, and can therefore become resistant to antibiotics
-WHO issued report outlining seriousness of development of resistant strains of organisms
-although rare, are infections that not treatable with currently available antibiotics
*refer to goodnote images

Question 25

Factors associated with antibiotic resistance

Answer 25

-2 major factors associated with development of antibiotic resistance: evolution of bacteria and clinical and environmental factors (ex. Misuse of antibiotics both clinically and in environment)

When have bacterial infection -> initial bacteria population is composed of a diverse array of batteries with different traits caused by mutations
-some bacteria traits make them resistance to certain antibiotics
-when antibiotic taken, the subset of bacteria that are sensitive to its effects will die, while bacteria resistant to effects will not
-over time these resistant bacteria replicate, forming new population and the traits given them antibiotic resistance will become common in entire population

Question 26

Antibiotics for the flu

Answer 26

-a common misconception is that antibiotics will help fight colds and the flu
-not the case though as the flu and common cold are caused by viruses
-taking antibiotics for cold or flu only contribute to the emergence of resistant bacteria

If given antibiotics when don’t need them, side effects could still hurt you
-rash, dizziness, nausea, diarrhea, yeast infections, and infection called Clostridium difficile (also called C. Difficile pr C. Diff)
-some antibiotics, called fluroquinolones, have special warnings about severe side effects. These powerful antibiotics are often prescribed even when aren’t recommended for treatment

Antibiotic resistance
-occurs when bacteria no longer respond to drug designed to kill them
-can make future infections harder to treat
-at least 2 million Americans get infected with antibiotic-resistant bacteria each year

-antibiotics don’t work on viruses like colds and flu, bronchitis, or runny noses
- antibiotics only needed for treating certain infections caused by bacteria
-wont help some common bacterial infections, including sinus infections and ear infections

Question 27

How did antibiotic resistance in E. Coli form

Answer 27

Since the mcg-1 gene was first identified in pigs, likely that this case of antibiotic resistance developed due to use of antibiotics in agriculture

Question 28

How organisms become resistant

Answer 28

-4 basic mechanisms for how they acquire resistance to antibiotics

Uptake
-small molecules gain access to inside of the microorganism by moving through pores of membrane
-mutation or lack of these pores make organism resistant

Target
-mutation in target for antibiotic can reduce binding of drug to its target and be ineffective

Inactivation
-microorganisms develop an enzyme that inactivates antibiotics
Ex. Formation of penicillinase, which inactivates penicillin

Effluent pumps
-some microorganisms over express transporters that pump drug out of microorganism before the cell can be injured

Question 29

Antifungal drugs

Answer 29

-incidence of serious fungal infections continues to increase, particularly in patients who required to take immunosuppressive drugs
-unfortunately, only a few highly effective antifungal drugs available

Echinochandins
-cell wall inhibitors: micafungin, caspofungin
-as inhibit wall, result in distruption of cell wall and fungal death
-commonly used
-very well tolerated in patients
-only available for intravenous administration

Imidazoles (or azoles)
Ergosterol synthesis inhibitors: ketoconazole, fluconazole, miconazole
-effective when taken orally or intravenously for systemic fungal infections
-these antifungals all inhibit a fungal cytochrome P450, thereby inhibiting ergosterol synthesis
-ergosterol critical for fungal cell wall function and survival
-selective toxicity of azoles lies in their higher affinity for fungal P450 than the human P450s that are involved in drug metabolism
-number of these ages (ex. Miconazole) are available as over-counter drugs for treatment of yeast infections

*refer to goodnotes for image

Question 30

What step in pharmacokinetics are P450s involved in and why don’t they interfere with this step when taken as an antifungal?

Answer 30

-in humans, P450 family of enzymes are responsible for metabolism of vast majority of clinically used drugs
- remember many drugs rely on selective toxicity

Selective toxicity of azoles lies in higher affinity for fungal P450 than human P450s that involved in drug metabolism
-this selective toxicity not perfect, however, imidazoles can sometimes cause drug-drug interactions by interfering with metabolism

Question 31

Viruses and antiviral drugs

Answer 31

-virus is small, infectious agent that only able to multiply within the living cells of other organisms, including animals, plants and bacteria
-viruses can be deadly and great need for additional and more effective antiviral drugs
-as such, efforts have been directed to synthesize and test new antiviral agents

Question 32

Viral cycle

Answer 32

-can serve as a mean of identifying targets for drug therapy of viral diseases
-current antiviral drugs act by targeting one or more of these viral life cycle steps
*refer to goodnotes for image and cycle

Question 33

TYPES OF ANTIVIRALS

Answer 33

-recent efforts have focused on developing antiviral drugs that more selective for their viral targets than initial therapies

Osetamivir ( brand name:tamiflu)
-neuraminidase inhibitor used to treat influenza
-neuraminidase is an enzyme that allows the spread of virus from cell to cell
-drugs of this class prevent neighbouring cells form being infected with virus

Acyclovir
-taken up into infected cells and virus activates the acyclovir to the active form
-active acyclovir then inhibits viral DNA replication
Thus acyclovir is selective for cells that are infected with the virus
-drug of choice for treatment of serious infections caused by herpes simplex virus (HSV)
-long-term use of acyclovir markedly decrease the frequency of recurrence of genital herpes
-also useful in combating infections due to varicella-zoster virus (VZV), the first that causes chickenpox adn shingles

Question 34

Difference between antivirals and vaccines

Answer 34

-general mechanism of action and when they are administered
Vaccines introduce non-functional fragments of the virus to the body prior to viral infections, such that the adaptive immune system is able to recognize and destroy the virus if it is introduced to the body
Vaccines are preventative, while antivirals treat infections already occurring in body

Question 35

What penicillinase resistant to action of penicillinase

Answer 35

Methicillin

Question 36

Co-trimoxazole combination of what drugs

Answer 36

Trimethoprim and sulfamethoxazole