Antibacterials and antivirals

Question 1

Define antibiotics, antibacterial, bacteriostatic and bacteriocidal

Answer 1

antibiotics - produced by fungi or bacteria that interferes with function, structure or processes essential for bacterial growth

antibacterials - synthetic antibiotics with same effects

bacteriostatic - stops bacterial growth

bacteriocidal - kills bacteria

Question 2

Types of antibacterials

Answer 2

antimetabolites
inhibitors of cell wall synthesis
interaction with plasma membrane
disruption of protein synthesis
inhibition of nucleic acid transcription and translation

Question 3

What is this

Answer 3

penicillin
derived from cysteine and valine

Question 4

What is its mechanism of action

Answer 4

inhibits transpeptidase enzyme which is responsible for crosslinking amino acid chains by forming covalent bond on enzymes active site

Question 5

Describe the chemistry of penicillin

Answer 5

Mimics 6-aminopenicilliniac acid (6APA)
Contains a beta lactam which mimics D-ala-D-ala terminal

Question 6

Explain the structure-activity relationship of penicillins

Answer 6

Strained beta lactam with 5 membered ring = unstable
Free CO2- for ionic interactions with NH2+ of lysine
Amide allows for bioavailability

Question 7

What is penicillin G

Answer 7

Is an analogue which contains a benzyl group on -R of the amide group

still prone to acid/base hydrolysis

Question 8

what are acid-sensitive penicillin

Answer 8

penicillin with no electron withdrawing side groups which makes the ring strained which is hydrolytically unstable

add a electron withdrawing to increase oral bioavailability

Question 9

What are acid-resistant penicillin

Answer 9

addition of electron withdrawing group on the side chain
PhO

Question 10

What are beta lactamase resistant penicillin

Answer 10

contain large steric shields to ward off lactamase enzymes

must use 2,6 disubstituted phenyl rings

Question 11

What are factors that affect susceptibility of penicillin

Answer 11

Structure of R group
Ability to cross outer cell membrane
Susceptibility to beta lactamases
Affinity for transpeptidase enzyme
Rate at which it is pumped out of the cell

Question 12

What are cephalosporins

Answer 12

Beta lactam antibiotics
They contain a 6 membered ring attached to a beta lactam = less sensitive

Question 13

Describe the structure of cephalosporin

Answer 13

Mimic 7-aminocephalosporinic acid (7-ACA)
Beta lactam mimics D-ala-D-ala terminal
3-methylene acetoxy can under esterase metabolic - formation of y-lactone = inactive drug

Question 14

Describe the structure of sulfonamides

Answer 14

Contains aniline - R and sulfonamide - R

amphoteric compounds with low aqueous solubility

Question 15

What is the mechanism of action of sulfonamides

Answer 15

Competitively inhibits dihydrofolate synthase which is an enzyme required for folate synthesis

Question 16

Explain the chemistry of sulfonamide

Answer 16

Mimics para-aminobenzoic acid (PABA) which is the substrate for dihydrofolate synthase

needs to be acidic in nature

Question 17

Explain the structure activity relationship of sulfonamides

Answer 17

p-NH2 mimics PABA and must be unsubstituted

Sulfonamide essential and must be primary or secondary

Aromatic ring must be p-sub

R group on sulfonamide
-aromatic sub = increase potency

Question 18

What are fluoroquinolones

Answer 18

Contain bicyclic ring and a metal chelating group

Question 19

What is the mechanism of action of fluoroquinolones

Answer 19

Interfere with bacterial nucleic acid transcription and replication

Stabilise DNA gyrase complex (supercoiling) and DNA topoisomerase IV complex (unravelling)

Question 20

Explain structure activity relationship of fluoroquinolones

Answer 20

3/4
For antibacterial activity
Have chelating effect

6
F group - essential for drug potency

7
Must be 5 or 6 membered nitrogen heterocycle

8
must be N, CCl or CF for expansion of spectrum

Question 21

Describe the chemistry of macrolides

Answer 21

natural product - very complex structures
-lactone ring with 14 carbons with 2 sugars
- converted into cyclic ketal in acidic environment

Question 22

What is the mechanism of action of macrolides

Answer 22

Interferes with protein synthesis by reversible binding to 50S subunit of ribosome

Question 23

What is the structure of a tetracycline

Answer 23

Contains 4 cyclic structure
Napthacene based
-functional groups, acidic enols and basic property
Can poly chelate ions

Question 24

What is the mechanism of action of a tetracycline

Answer 24

Interferes with bacterial protein synthesis via reversible binding to 30S subunit of ribosome

Question 25

What are some resistance mechanism and do we combat them

Answer 25

Penicillin resistance
Physical barriers
Beta lactamases - use beta lactam inhibitors
Efflux pumps - pump antibiotics out
Mutations and genetic transfers

Sulfonamide resistance
Synthesis of larger amounts of PABA
Mutation of target enzymes
Mutation to decrease cell membrane permeability
-use higher doses

Question 26

What are viruses

Answer 26

Non-cellular infectious agents that requires a host to survive

Structure
Nucleic acid core
Nucleocapsid - protein coat
Glycoprotein membrane that surround capsid

Question 27

Explain the viral life cycle

Answer 27

Adsorption/ attachment onto cell by binding to cellular glycoprotein

Penetration and uncoating which enters and releases viral nucleic acid as well as enzymes

Replication and transcription of viral nucleic acid and proteins

Synthesis and assembly of nucleocapsid

Virion release via budding or cell lysis

Question 28

Explain how inhibitors of viral DNA polymerase work

Answer 28

They block nucleic acid synthesis by having an incomplete sugar backbone which prevents linking of nucleotides
-missing OH

Question 29

Explain the mechanism of action of aciclovir

Answer 29

Mimic deoxyguanosine triphosphate that lacks OH group on the sugar backbone

Requires viral thymidine kinase to initiate first phosphorylation
Cellular kinase will phosphorylate to triphosphate where it becomes active

Question 30

Give examples of aciclovir analogues

Answer 30

Valaciclovir
- contains valyl side chain
- increased absorption in gut

Famciclovir
- more lipophilic
- better absorption

Ganciclovir
- contains hydroxymethylene group
- allows for parenteral administration

Cidofovir
- contains phosphomethylene group
- doesn’t require viral thymidine kinase for first phosphorylation

Question 31

Explain the viral RNA cycle

Answer 31

Protease dissolves nucleocapsid after entry into host cell

Release of viral RNA and enzymes

Viral reverse transcriptase converts RNA to DNA then incorporated into host DNA by viral integrase

Transcription produces viral RNA

New virus released from host cells

Question 32

Nucleoside reverse transcriptase

Answer 32

Similar mechanism of action to aciclovir
No OH group at terminal

Question 33

Give examples of nucleoside reverse transcriptase analogues

Answer 33

Zidovudine
- deoxythymidine analogue
- N3 terminating group

Lamivudine
- deoxycytidine analogue
- S terminating group

Didanosine
- contains inosine
- no OH group

Question 34

What are non-nucleoside reverse transcriptase NNRT

Answer 34

They are hydrophobic molecules that non competitively bind to allosteric binding site which

Highly selective for HIV1 reverse transcriptase

Question 35

What are some examples of NNRT

Answer 35

Delaviridine
Nevirapine
Capravirine

Question 36

What are proteases

Answer 36

They are proteins secreted by viruses, its mechanism of action is to dissolve viral nucleocapsid upon entry into host cell

Cleave peptide bond between proline and aromatic amino acid

Question 37

What is the mechanism of action of protease inhibitors

Answer 37

Mimic tetrahedral transition state of protease which binds stronger than substrate or product