Lecture 8

Question 1

Antimicrobial agents are used:

Answer 1

to treat diseases by destroying pathogenic microorganisms or inhibiting their growth at concentrations low enough to avoid undesirable damage to the host

Question 2

When was penicillin discovered?

Answer 2

1928

Question 3

When was sulfonamides discovered?

Answer 3

1935

Question 4

When was penicillin first used in clinical as an effective therapeutic substance?

Answer 4

1940

Question 5

When was the Streptomycin antibiotic discovered from Streptomyces bacterial species?

Answer 5

1944

Question 6

Today, 80% of antibiotics are sourced from the bacterial genus __

Answer 6

Streptomyces, actinomycetes

Question 7

Ideal antimicrobial drugs exhibit _____, which means the drug is harmful to a pathogen without being harmful to the host

Answer 7

selective toxicity

Question 8

Antimicrobial drugs act in one of the following ways:

Answer 8

1) Inhibition of cell wall synthesis
2) Inhibition of cell membrane function
3) Inhibition of protein synthesis
4) Inhibition of nucleic acid synthesis

Question 9

How do antimicrobial drugs act to inhibit cell wall synthesis?

Answer 9

The antibiotics inhibit transpeptidation enzymes ( such as PBPs) involved in the building of peptidoglycan layers of the cell wall (by cross-linking of NAG-NAM polysaccharide chain)
As a result, incomplete cell wall builds and cell will lyse and die

Question 10

What is an example of antibiotics that inhibit cell wall synthesis?

Answer 10

All Beta-lactam antibiotics (penicillin, ampicillin, cephalosporins, cephamycin, carbapenems, etc.) are selective inhibitors of bacterial cell wall synthesis

Question 11

After inhibiting the transpeptidation reaction, some of the Beta-lactam drugs are involved in the:

Answer 11

inactivation of inhibitors of autolytic enzymes in the cell wall –> the activation of the lytic enzymes leads to cell wall lysis

Question 12

Do Gram + and Gram - bacteria have different susceptibilities to Beta-lactam antibiotics?

Answer 12

Yes, due to structural differences in their cell walls

Question 13

______ drugs show a remarkable lack of toxicity to mammalian cells

Answer 13

Beta-lactam

Question 14

Other antibiotics target cell wall synthesis, such as:

Answer 14

vancomycin, bacitracin, and novobiocin, and other glycopeptide analogues such as teicoplanin and cycloserine

Question 15

Why do some pathogens show resistance to Beta-lactam antibiotics?

Answer 15

Their ability to produce Beta-lactamases ( or penicillinases) enzymes that inhibit or destroy Beta-lactam compounds

Question 16

What are some examples of Beta-lactamases that are plasmid-mediated?

Answer 16

Penicillinase, Staphyloccus aureus, Neisseria gonorrhoeae, Haemophilus influenzae, and Enterococci

Question 17

What are some examples of Bet-lactamases that are chromosomally mediated?

Answer 17

Bacteroides, Acinetobacter, Enterobacter, and Pseudomonas species

Question 18

A group of B-lactamases termed: ________ confer additional resistance to more B-lactam drugs such as cefotaxime, ceftazidime, or aztreonam

Answer 18

extended-spectrum B-lactamases (ESBLs)

Question 19

ESBLs are produced by certain species of Gram-negative bacilli, such as:

Answer 19

Klebsiella pneumoniae, and Escherichia coli

Question 20

Clavulanic acid, sulbactam, and tazobactam are ________

Answer 20

B-lactamase inhibitors

Question 21

How do Beta-lactamase inhibitors work?

Answer 21

They have a high affinity for Beta-lactamases enzymes, they can bind to them and inhibit them rendering them Beta-lactam resistant pathogen sensitive to Beta-lactam drugs

Question 22

Inhibition/alteration of cell membrane function:
Polymixins:

Answer 22

disrupt membrane structure and permeability properteries

Question 23

Inhibition/alteration of cell membrane function:
Nalidixic acid and novobiocin:

Answer 23

Interfere with biosynthetic functions of the cell membrane and inhibit teichoic acid synthesis

Question 24

Inhibition/alteration of cell membrane function:
Ionophores (Valinomycin):

Answer 24

permit rapid diffusion of specific cations (such as potassium ions) through the membrane

Question 25

Inhibition/alteration of cell membrane function: Daptomycin:

Answer 25

-A lipopeptide antibiotic -It is rapidly bactericidal, it binds to the cell and can cause depolarization of the bacterial membrane. This leads to intracellular potassium release that causes cell death

Question 26

Inhibition of protein synthesis: Aminoglycosides (Streptomycin and Gentamycin):

Answer 26

bind with the 30S subunit of the bacterial ribosome causing misreading of mRNA and inhibiting protein synthesis

Question 27

Inhibition of protein synthesis: Macrolides, Azalides, Ketolides and Lincosamide drugs:

Answer 27

-Erythromycins, azithromycin, clarithromycin, roxithromycin and ketolide telithromycin and the lincosamide clindamycin bind to the 50S subunit and inhibit the peptide chain elongation

Question 28

Inhibition of protein synthesis: Tetracyclines:

Answer 28

bind reversibly to the 30S subunit of microbial ribosomes and interfere with aminoacyl-tRNA binding

Question 29

Inhibition of protein synthesis: Chloramphenicol:

Answer 29

-Binds to the 50S subunit -It interferes with the binding of new amino acids to the nascent peptide chain, through inhibiting peptidyl transferase -Chloramphenicol is mainly bacteriostatic

Question 30

Inhibition of protein synthesis: Oxazolidinones:

Answer 30

-Process a unique mechanism of inhibition of protein synthesis in Gram-positive bacteria -They interfere with translation by inhibiting the formation of N-formyl methionyl tRNA, the initiation complex at the 23S ribosome

Question 31

What is the first antibiotic of the Oxazolidinone group to be commercially available and what is it used to treat?

Answer 31

-Linezolid -It is used to treat infections caused by vancomycin-resistant Enterococci and even Mycobacterial infections

Question 32

Inhibition of nucleic acid synthesis: Rifampin:

Answer 32

Binds strongly to the DNA-dependent RNA polymerase of bacteria. It blocks bacterial RNA synthesis

Question 33

Inhibition of nucleic acid synthesis: Quinolones and fluoroquinolones:

Answer 33

Inhibit bacteria DNA gyrases (topoisomerase) thus interfere with DNA replication, transcription, and DNA repair mechanisms

Question 34

Inhibition of nucleic acid synthesis: Sulfonamides, trimethoprim, and pyrimethamine:

Answer 34

Inhibit of synthesis of nucleic acids

Question 35

Aminoglycosides-resistant pathogens produce:

Answer 35

adenylating, phosphorylating, or acetylating enzymes that destroy the drug

Question 36

How do microorganisms change their permeability to the drug?

Answer 36

Through down-regulation of porin channels required for Beta-lactam entry. (Ex: Enterobacter spp., Klebsiella pneumoniae, and Escherichia coli) They exhibit resistance to carbapenem antibiotics based on the loss of these porin channel proteins Resistance to polymyxins is also associated with a change in permeability to the drugs

Question 37

Streptococci have a natural permeability barrier to ________

Answer 37

aminoglycoside antibiotics

Question 38

Microorganisms develop an altered structural target for the drug in two ways (explain):

Answer 38

A) Modification in PBPs (mutation or expression of alternative PBPs): This can lower the ability of Beta-lactam antibiotics to bind to PBPs in the bacterial cell wall. Ex: PBPs of Methicillin-resistant Staphylococcus aureus (MRSA). Streptococcus pneumonia, and Neisseria spp --> have acquired highly resistant and low affinity PBPs B) Erythromycin-resistant organisms: have altered receptors on the 50S subunit of the ribosome

Question 39

Microorganisms develop an altered enzymes that can still preform its metabolic function but is much _____ affected by the drug

Answer 39

less

Question 40

In Trimethoprim resistant bacteria, the _____ (involved in nucleic acid synthesis) is inhibited far less effectively than in trimethoprim susceptible bacteria

Answer 40

dihydrofolic acid reductase

Question 41

In some multidrug-resistant Gram-negative pathogens (Ex: Pseudomonas aeruginosa and Acinetobacter spp.) the ___________ in concert with low membrane permeability confers resistance to penicillin and cephalosporins as well as other antibiotics

Answer 41

upregulation of efflux pumps