Lecture 8: anti-infectives

Question 1

Microorganism

Answer 1

Cellular(living): parasites, protozoa, fungi, prokaryote

Acellular(non-living): Virus, prion

Question 2

Classification of Bacteria

Answer 2

Shape:
Spheres(Cocci)
Rods(bacilli)
Spirals
Cell wall
Gram-positive: Thicc peptidoglycan, and a single PM
Gram-negative: Thin peptidoglycan between two PM

Question 3

Classification of Antibiotics

Answer 3

Bactericidal-kill bacteria

Bacteriostatic-stop bacteria from reproducing or inhibit growth(not kill)

Question 4

3 general classes of potential targets

Answer 4

Class I: generation of ATP and simple carbon compounds
Broad so therefore poor targets

Class II: energy-dependent synthesis of amino acids, nucleotides and phospholipids

Class III: formation of macromolecules RNA, DNA and peptidoglycan

Question 5

Class 2: Folate biosynthesis

Answer 5

Folate biosynthesis:
Folate FH4 required for DNA synthesis
Human can only get folate from diet
Bacteria cannot take up folate so need de novo synthesis

Question 6

Sulfonamides

Answer 6

Inhibit folate synth by competitively inhibiting dihydropteroate synthetase(PABA–>Folate)

Question 7

Trimethoprim

Answer 7

Much more potent inhibitor of dihydrofolate reductase(Folate->Tetrahydrofolate) in bacterial enzymes vs human
Bacteriostatic
Given with sulfamethoxazole(a sulfonamide)=synergistic action
Resistance: due to altered dihydrofolate reductase

Note: methotrexate inhibs both human and bacteria, but bacteria cannot take up

Question 8

Class 3 reaction: Bacterial cell wall synthesis

Answer 8

Peptidoglycan: major component of bacterial cell wall, not found in eukaryotic cells
Backbone of amino sugar
N-acetyl muramic acid and N-acetylglucoasmine
Peptide side-chains, cross-linked to form lattice

Question 9

Beta-lactam antibiotics

Answer 9

Bactericidal
Covalently bond to penicillin-binding proteins(PBPs) in cytoplasmic membrane
Inhibit cross-linking of peptide chains attached to the peptidoglycan backbone
Inactivate inhibitors of autolysis
PBPs unique to each bacteria species = diff sensitivity to drugs
Examples

Question 10

Penicillins

Answer 10

First antibiotic isolated from micro-organisms
Broad spectrum, still given for a wide range of infections
Wide forms of synthetic and semi-synthetic forms
Ex. Amoxicillin used with clarithromycin(macrolides) and omeprazole in treatment of H. pylori
Contain Beta-lactam ring: Susceptible to Beta-lactamase=resistance

Question 11

Flucloxacillin

Answer 11

still active if B-lactamase present

Question 12

Clavulanic acid

Answer 12

high affinity inhibitor of Beta-lactamase

Question 13

Beta-lactam antibiotics: 4 main groups

Answer 13

Penicillin nucleus

Cephalosporin nucleus: isolated from cephalosporium fungus, 1-4 generations
Same mech as penicillins, broad spectrum
Ex. Cefotaxime

Monobactam nucleus-resistant to lactamases-same mech as penicillins

Carbapenem nucleus-resistant to lactamases-same mech as penicillins

Question 14

Class 3 reaction: Bacterial protein synthesis

Answer 14

Selective based on differences between mammalian and bacterial ribs
Bacterial ribs have 50S* and 30S subunits
Mammalian ribs have 60S and 40S subunits
3 groups are bacteriostatic(TAM)
Tetracyclines
Amphenicols
Macrolides
1 group is bactericidal***= Aminoglycosides

Question 15

Tetracyclines

Answer 15

Compete with tRNA for binding to ribosomes-inhibits tRNA binding
Static, broad specturm, selective via uptake by transporter

Use decline bc resistance: decrease accumulation bc increase efflux or decrease uptake, enzymatic inactivation of drug
Chelator of divalent ions: not taken with dairy food, deposit in bone and teeth-not gien children

Question 16

Amphenicols

Answer 16

Mechanism: inhibit transpeptidation
Static
Also binds 70S of mammalian ribs to inhibit protein synthesis
Marrow suppression, grey baby syndrome(unable to metabolize drugs)
Resistance due to increased drug breakdown

Question 17

Macrolides

Answer 17

Mechanism: interfere with translocation

Ex. erythromycin
Static-inactive against most gram (-)
Can inhibit CYP3A4 = drug interaction
Resistance: 
Drug efflux or breakdown
Change in ribosomal binding site

Question 18

Aminoglycosides

Answer 18

Mechanism: interfere with mRNA binding leading misreading of mRNA so wrong aa inserted
Bactericidal-defective protein in membrane

Ex. Streptomycin

Resistance: ribosomal changes, decrease influx or increased breakdown

Question 19

Class 3: bacterial nucleic acid synthesis

Answer 19

DNA exist as a negative supercoil-replication inserts positive supercoil which must be relaxed into negative supercoil by:

DNA gyrase type 2 topoisomerase=essential for replication, different to mammalian enzymes

Question 20

Fluoroquinolones

Answer 20

nhibit DNA gyrase and so inhibit replication
Ex. Ciprofloxacin
Binds to catalytic site on enzyme
Broad spectrum
Used commonly for GIT infection, travellers diarrhea, UTI’s
Bactericidal-once rep starts, doesn’t complete and cell dies