Lecture 7 - Chemistry of Antimicrobial agents Flashcards
Antibacterial drugs are able to?
kill or inhibit the growth of microbes at low concentrations
How do antibacterial drugs work?
selectively
What drugs target cell wall synthesis?
Beta lactams glycopeptides cycloserine bacitracin fosfomycin
What drugs target DNA gyrase?
quinolones
What drugs target RNA polymerase?
rifamycins
What drugs are 50S inhibitod?
macrolides
chloramphenicol
clindamycin
linezolid
streptogramins
What drug are 30S inhibitors?
tetracyclines
aminoglycosides
What drugs target tRNA?
mupirocin
What drugs target cytoplasmic membrane structure?
polymyxins
daptomycin
What drugs target folic acid metabolism?
trimethoprim
sulfonamides
What do porins in gram negative cell walls allow?
a way for small antibiotics of low MWt to enter inside the gram negative and target the peptidoglycan
What causes cross linking of the peptide chains in the cell wall?
penicillin binding proteins (PBPs)
What does the cross linking achieve?
a more rigid structure
What is there at the end of the peptic chain?
2 molecules of alanine
What is the peptidoglycan composed of?
N-acetylglucosamine (NAG)
N-acetylmuramic acis (NAM)
D-alanine (D-Ala)
What are the 4 classes of the beta lactam antibiotics?
penicillin
cephalosporin
carbapenem
monobactam
What structure do the beta lactams contain?
4 membered cyclic amide
What is a natural substrate for the penicillin binding proteins?
alanine
What is the mode of action of beta lactams?
PBP bind to the beta lactams, at forms a complex
this means the enzyme is no longer available to form the peptidoglycan as normal and the synthesis is inhibited
the bacterial wall no longer has a rigid structure and will be killed
What does beta lactam-PBP complexation lead to?
irreversible inhibition of cross linking and bacterial cell lysis
What are beta lactams?
bactericidal
Why is a primary amide stable?
the electrons from the lone pair ca delocalise and move towards the O of the carbonyl, resulting in mesmeric form which always has a double bond tendency
Why is penicillin not very stable?
the structure is not planar and the cyclic amide is very constrained and wants to break open
Why are beta lactams very reactive?
the electrons of the lone pair cannot delocalise properly because there is no planarity
the bond can quickly open and if it is broken, the beta lactam structure is degraded and there is total loss of antibiotic activity
What does penicillin come from?
penicillium mould which is a fungus
discovery made by Alexander Fleming
What are the classes of penicillins?
narrow spectrum
broad spectrum
antipseudomonal
What are the divisions of narrow and broad spectrum penicillins?
beta lactamase resistant
beta lactamase sensitive
What do narrow spectrum penicillins work on?
gram positives
What do broad spectrum penicillins work on?
gram positive and gram negatives
What types of penicillins are there?
synthetic and natural
oral parenteral
What are all natural penicillins?
very reactive and degrade very easily in water
facilitated in the presence of protons in acidic medium
What can a molecule of water attack?
positive delta plus charged carbon of the carbonyl function, leads to a complete opening of the beta lactam ring
What does nucleophilic attack in acidic medium do?
oxygen attacks the carbonyl and there is degradation, the beta lactam ring is no longer there
What does attaching an electronegative group to the left side chain do?
minimises neighbouring group attack on the beta lactam carbonyl
pulls the electrons away from the oxygen
Narrow spectrum penicillins?
benzylpenicillin
phenoxymethyl penicillin
Benzylpenicillin?
does not contain an electronegative group so is very unstable and cannot be given in acidic medium (orally)
Phenoxymethyl penicillin?
contains an additional oxygen which is electronegative and is enough to make is less susceptible to degradation
can be given orally
What are beta lactamases?
proteins which are produced by bacteria in response to being treated with a beta lactam antibiotic
What do beta lactamases do?
cleave the beta lactam ring, breaking the bat lactam cycle and make the antibiotic totally inactive
What is flucloxacillin?
resistant to beta lactamases
Why is flucloxacillin resistant to beta lactamases?
it contains an aromatic cycle (bulky side chain) which will act like a protective shield should a beta lactamase enzyme come near the carbon atom
the presence of the side chain acts like an umbrella to protect the beta lactam from attack
If flucloxacillin broad or narrow spectrum?
narrow spectrum
works very well on gram positive
What is flucloxacillin used for?
used as the treatment of choice in staph aureus infections involving skin and soft tissue
When is temocillin used?
in the presence of beta lactamases
Structure of temocillin?
in position 6 of the beta lactam ring there is an additional O methyl and this is enough to protect the carbonyl and will act like a hindrance to the beta lactamase enzyme
What do beta lactamase inhibitors do?
bind covalently to beta lactamases
Examples of beta lactamase inhibitors?
clavulanic acid and tazobactam
Co-amoxiclav?
Augmentin = amoxicillin + clavulanic acid
Tazocin?
Piperacillin + tazobactam
What do beta lactamase inhibitors look like?
very similar to beta lactams but do not have the side chain on the left
What does ampicillin have?
additional electronegative group (NH2) so it can be taken orally
What does amoxicillin have?
Additional electronegative group (NH2) and an additional hydroxyl group
Broad spectrum penicillins?
Amipicillin and amoxicillin
hydrophilic and have low Mwt so can go through the porins of gram negative
Penicillins that work on pseudomonas aeruginosa?
ticarcillin and piperacillin
How can ticarcillin and piperacillin be given?
not orally
they do not have electronegative groups on the side chains
Gram positive active cephalosporins?
cefalexin, cefradine, cefadroxil, defaclor
Beta lactamase resistant cephalosporins?
cefuroxime
Gram negative active cephalosporins and beta lactamase resistant?
cefotaxime, ceftriaxone, cefixime, cefpodoxime
Cephalosporins active against pseudomonas aeruginosa and beta lactamase resistant?
Ceftazidime
Natural cephalosporins?
easily degraded
Oral (acid stable) cephalosporins?
cefalexin and cefaclor
Parenteral cephalosporins?
ceftazidime
What does ceftazidime contain?
zwitterion
has both charges at physiological pH
not easily absorbed through membranes as it is not lipophilic
Beta lactamase resistant cephalosporins?
cefuroxime
contains an extra substituent on the side chain - presence of this is enough to protect the beta lactam and creates a hindrance - means it will not be easily attacked by beta lactamases
cefixime
Anti-pseudonmonal cephalosporins?
ceftazidime
has the quaternary ammonium making it active on pseudomonas
What are the aims of drug development of penicillins?
Aim 1 - increase stability in acidic medium
Aim 2 - resistance to beta lactamases
Aim 3 - spectrum of activity
