Antibacterials and antivirals Flashcards
Define antibiotics, antibacterial, bacteriostatic and bacteriocidal
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
Types of antibacterials
antimetabolites
inhibitors of cell wall synthesis
interaction with plasma membrane
disruption of protein synthesis
inhibition of nucleic acid transcription and translation
What is this
penicillin
derived from cysteine and valine
What is its mechanism of action
inhibits transpeptidase enzyme which is responsible for crosslinking amino acid chains by forming covalent bond on enzymes active site
Describe the chemistry of penicillin
Mimics 6-aminopenicilliniac acid (6APA)
Contains a beta lactam which mimics D-ala-D-ala terminal
Explain the structure-activity relationship of penicillins
Strained beta lactam with 5 membered ring = unstable
Free CO2- for ionic interactions with NH2+ of lysine
Amide allows for bioavailability
What is penicillin G
Is an analogue which contains a benzyl group on -R of the amide group
still prone to acid/base hydrolysis
what are acid-sensitive penicillin
penicillin with no electron withdrawing side groups which makes the ring strained which is hydrolytically unstable
add a electron withdrawing to increase oral bioavailability
What are acid-resistant penicillin
addition of electron withdrawing group on the side chain
PhO
What are beta lactamase resistant penicillin
contain large steric shields to ward off lactamase enzymes
must use 2,6 disubstituted phenyl rings
What are factors that affect susceptibility of penicillin
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
What are cephalosporins
Beta lactam antibiotics
They contain a 6 membered ring attached to a beta lactam = less sensitive
Describe the structure of cephalosporin
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
Describe the structure of sulfonamides
Contains aniline - R and sulfonamide - R
amphoteric compounds with low aqueous solubility
What is the mechanism of action of sulfonamides
Competitively inhibits dihydrofolate synthase which is an enzyme required for folate synthesis
Explain the chemistry of sulfonamide
Mimics para-aminobenzoic acid (PABA) which is the substrate for dihydrofolate synthase
needs to be acidic in nature
Explain the structure activity relationship of sulfonamides
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
What are fluoroquinolones
Contain bicyclic ring and a metal chelating group
What is the mechanism of action of fluoroquinolones
Interfere with bacterial nucleic acid transcription and replication
Stabilise DNA gyrase complex (supercoiling) and DNA topoisomerase IV complex (unravelling)
Explain structure activity relationship of fluoroquinolones
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
Describe the chemistry of macrolides
natural product - very complex structures
-lactone ring with 14 carbons with 2 sugars
- converted into cyclic ketal in acidic environment
What is the mechanism of action of macrolides
Interferes with protein synthesis by reversible binding to 50S subunit of ribosome
What is the structure of a tetracycline
Contains 4 cyclic structure
Napthacene based
-functional groups, acidic enols and basic property
Can poly chelate ions
What is the mechanism of action of a tetracycline
Interferes with bacterial protein synthesis via reversible binding to 30S subunit of ribosome
What are some resistance mechanism and do we combat them
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
What are viruses
Non-cellular infectious agents that requires a host to survive
Structure
Nucleic acid core
Nucleocapsid - protein coat
Glycoprotein membrane that surround capsid
Explain the viral life cycle
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
Explain how inhibitors of viral DNA polymerase work
They block nucleic acid synthesis by having an incomplete sugar backbone which prevents linking of nucleotides
-missing OH
Explain the mechanism of action of aciclovir
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
Give examples of aciclovir analogues
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
Explain the viral RNA cycle
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
Nucleoside reverse transcriptase
Similar mechanism of action to aciclovir
No OH group at terminal
Give examples of nucleoside reverse transcriptase analogues
Zidovudine
- deoxythymidine analogue
- N3 terminating group
Lamivudine
- deoxycytidine analogue
- S terminating group
Didanosine
- contains inosine
- no OH group
What are non-nucleoside reverse transcriptase NNRT
They are hydrophobic molecules that non competitively bind to allosteric binding site which
Highly selective for HIV1 reverse transcriptase
What are some examples of NNRT
Delaviridine
Nevirapine
Capravirine
What are proteases
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
What is the mechanism of action of protease inhibitors
Mimic tetrahedral transition state of protease which binds stronger than substrate or product
