Dugga 3 Antibiotics Flashcards
What are the five main targets if antibacterial agents?
Cell metabolism, the cell wall, the plasma membrane, protein synthesis, nucleic acid function
What do sulphonamides require to function?
Primary aromatic amine group and a secondary sulphonamide group for good activity
What is a common metabolic reaction of sulphonamides?
N-acetylation
What are sulphonamides used for?
Treating infections of urinary tract, gastrointestinal tract and mucous membranes. Also in eye lotion
Which structure is sulphonamides similar to?
PABA para amino benzoic acid which is necessary for bacteria to bind to an enzyme to synthesise dihydroteroate. They act as a competitive inhibitor
What are sulphonamides an example of? (Which class of antibiotic is it?)
Antimetabolite, antibacterial agent that act against cell metabolism
Give 3 examples of antimetabolites
Sulphonamides, trimethoprim, sulphones
Give examples of antibacterial agents that inhibit cell wall synthesis
Penicillin
What is the structure of penicillin? How does it react?
Bicycling with a beta lactam ring fused to a thiazolidone ring. The beta lactam ring reacts irreversibly with the transpeptidase enzyme that cross links the bacterial cell wall.
How can penicillin be made more resistant to acid conditions?
By incorporating an electron withdrawing group into the acyl side chain
How can penicillin be protected from beta lactamase enzymes?
By adding steric shields
What structure gives the penicillin broad spectrum activity?
The alpha hydrophilic group on the acyl side chain
What are prodrugs of penicillin useful for? Which structures are used?
Masking polar groups to imported the absorption from GI tract. Extended esters are used
What groups does penicillin contain?
A highly unstable bicyclic system of a strained four membered beta lactam ring fused to a five membered thiazolidine ring
What amino acids does the skeleton structure of penicillin suggest to be derived from?
Cysteine and valine
Benzylpenicillin (Penicillin G) cannot be taken orally, why?
It is broken down by stomach acids and must be injected
Benzylpenicillin is ineffective against which types of bacteria?
Gram negative and those that produce beta lactamase
What does penicillin target?
The enzyme transpeptidase, responsible for interlinking during cell wall synthesis
What is the bacteria cell wall made up of?
Peptidoglycan structure made up of NAM and NAG
Penicillin has a conformation similar to the transition state conformation of what moiety during crosslinking?
D-Ala-D-Ala
Do bacteria have both D and L amino acids?
Bacteria have racemase that can convert L amino acids into D amino acids
What is the most important way bacteria gain resistance to penicillin?
Beta lactamase enzymes
Most if not all Gram negative bacteria produce what that makes them more resistant to penicilin?
Beta lactamase enzymes
What was originally the only way to prepare different penicillins?
By varying fermentation conditions
Which methods are used now to produce different penicillins?
Semi synthesis
What is the SAR of penicillin?
The beta lactam ring is essential
Free carboxylic acid essential (usually ionised and penicillins administered as sodium salts)
Bicyclic system
6-acyl-amino side chain
Sulphur usual but not essential
Stereochemistry of the bicyclic ring with respect to the acylamino side chain important
Why is penicillin G acid sensitive?
Ring strain
Highly reactive beta lactam carbonyl group
INfluence of the acyl side chain
How can penicillin be made acid resistant?
Placing an electron withdrawing group in the side chain to draw electrons away from carbonyl oxygen and reduce the tendency to act as a nuclephile
Penicillin V has an electronegative O on the acyl side chain and can be given orally
How are beta lactamase resistant penicillin made?
Steric shield, adding a bulky group on the side chain (but not too bulky so the penicillin couldn’t bind target)
Nafcillin and Temocilin (reserve troops)
What are broad spectrum penicillins?
Having activity against both gram positive and negative bacteria
What is used as first line of defense against infection?
Ampicillin and amoxicillin
Mention three types of broad spectrum penicillins
Ueridopenicillin, aminopenicillin and carboxypenicillin
Mention another type of antibiotic than penicilin
Cephalosporin, it has a similar bicyclic system with a four membered ring and then a six membered ring
What advantages do first generation cephalosporins have over penicillin?
Greater stability to acid conditions (stomach) and resistance towards beta lactamases and effective against both gram negative and positive, but lower activity
How can semi-synthetic cephalosporins be prepared?
From 7-ACA (aminocephalosporanic acid)
How is 7-ACA obtained?
From hydrolysis of cephalosporins
What type of cephalosporins have increased potency?
Oximinocephalosporins
What other beta lactam antibiotics exist?
Carbapenems, monobactams
What are beta lactamase inhibitors and what are they used for?
Given together with antibiotics such as penicillin, they inhibit the beta lactamase enzymes so that the penicillin will work
Mention two beta lactamase inhibitors
Avibactam and Clavulanic acid
Mention other classes of antibacterial agents that act on the biosynthesis of the cell wall, besides penicillin and cephalosporins
Vanomycin, D-cycloserine and bacitracin
How does vancomycin work?
It is a glycopeptide that binds to the building blocks for cell wall synthesis preventing incorporation of the blocks into the cell wall
What antibacterial agents are the last resort against drug resistant bacterial strains?
Glycopeptides such as vancomycin
How does valinomycin and gramicidin work against bacteria?
They are ion-conducting antibiotics (ionophores) and allow uncontrolled movement of ions across the call membrane
Are cyclic lipopeptides a new class of antibiotics?
Yes
Do valinomycin and gramicidin A show selective toxicity for bacterial cells over mammalian cells?
No and therefore useless as systemic therapeutic agents
How do antibacterial agents that impair protein synthesis show selectivity for bacterial cells over mammalian?
Because bacterial cells have a 70S bacterial ribosome consisting of 30S subunit and 50S subunit. Mammals have 80S consisting of 60S and 40S.
Give an example of an antibacterial agent working in disrupting protein synthesis
Streptomycin (aminoglycoside), tetracyclines, chloramphenicol, macrolides, lincosamides, streptogramins, oxazolidinones, pleuromutilins
Why has widespread resistance to tetracyclines occured?
Because they have been used in farming to promote growth of newborn animals
Give an example of an antibacterial agents that act on nucleic acid transcription and replication
Quinolones and fluoroquinolones
Aminoacridines
Rifamycins
Nitroimidazoles and nitrofurantoin
How do quinolones work?
They inhibit topoisomerase enzymes which means replication and transcription is inhibited
How do aminoacridines work?
They intercalate with bacterial DNA and hinder replication and transcription
How do rifamycins work?
They inhibit the enzyme RNA polymerase and prevent RNA synthesis which prevents protein synthesis
What are nitoimidazoles used for?
Infections caused by protozoa and anaerobic bacteria
How is drug resistance transfered by genetic transfer?
Transduction or conjugation
How does transduction work?
Plasmids transfered by bacteriophages with gene for resistance
Are some bacterial strains quicker to gain resistance than others?
Yes
