Lecture 7 - Chemistry of Antimicrobial agents

Question 1

Antibacterial drugs are able to?

Answer 1

kill or inhibit the growth of microbes at low concentrations

Question 2

How do antibacterial drugs work?

Answer 2

selectively

Question 3

What drugs target cell wall synthesis?

Answer 3

Beta lactams 
glycopeptides
cycloserine 
bacitracin 
fosfomycin

Question 4

What drugs target DNA gyrase?

Answer 4

quinolones

Question 5

What drugs target RNA polymerase?

Answer 5

rifamycins

Question 6

What drugs are 50S inhibitod?

Answer 6

macrolides

chloramphenicol

clindamycin

linezolid

streptogramins

Question 7

What drug are 30S inhibitors?

Answer 7

tetracyclines

aminoglycosides

Question 8

What drugs target tRNA?

Answer 8

mupirocin

Question 9

What drugs target cytoplasmic membrane structure?

Answer 9

polymyxins

daptomycin

Question 10

What drugs target folic acid metabolism?

Answer 10

trimethoprim

sulfonamides

Question 11

What do porins in gram negative cell walls allow?

Answer 11

a way for small antibiotics of low MWt to enter inside the gram negative and target the peptidoglycan

Question 12

What causes cross linking of the peptide chains in the cell wall?

Answer 12

penicillin binding proteins (PBPs)

Question 13

What does the cross linking achieve?

Answer 13

a more rigid structure

Question 14

What is there at the end of the peptic chain?

Answer 14

2 molecules of alanine

Question 15

What is the peptidoglycan composed of?

Answer 15

N-acetylglucosamine (NAG)
N-acetylmuramic acis (NAM)
D-alanine (D-Ala)

Question 16

What are the 4 classes of the beta lactam antibiotics?

Answer 16

penicillin

cephalosporin

carbapenem

monobactam

Question 17

What structure do the beta lactams contain?

Answer 17

4 membered cyclic amide

Question 18

What is a natural substrate for the penicillin binding proteins?

Answer 18

alanine

Question 19

What is the mode of action of beta lactams?

Answer 19

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

Question 20

What does beta lactam-PBP complexation lead to?

Answer 20

irreversible inhibition of cross linking and bacterial cell lysis

Question 21

What are beta lactams?

Answer 21

bactericidal

Question 22

Why is a primary amide stable?

Answer 22

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

Question 23

Why is penicillin not very stable?

Answer 23

the structure is not planar and the cyclic amide is very constrained and wants to break open

Question 24

Why are beta lactams very reactive?

Answer 24

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

Question 25

What does penicillin come from?

Answer 25

penicillium mould which is a fungus discovery made by Alexander Fleming

Question 26

What are the classes of penicillins?

Answer 26

narrow spectrum broad spectrum antipseudomonal

Question 27

What are the divisions of narrow and broad spectrum penicillins?

Answer 27

beta lactamase resistant beta lactamase sensitive

Question 28

What do narrow spectrum penicillins work on?

Answer 28

gram positives

Question 29

What do broad spectrum penicillins work on?

Answer 29

gram positive and gram negatives

Question 30

What types of penicillins are there?

Answer 30

synthetic and natural oral parenteral

Question 31

What are all natural penicillins?

Answer 31

very reactive and degrade very easily in water facilitated in the presence of protons in acidic medium

Question 32

What can a molecule of water attack?

Answer 32

positive delta plus charged carbon of the carbonyl function, leads to a complete opening of the beta lactam ring

Question 33

What does nucleophilic attack in acidic medium do?

Answer 33

oxygen attacks the carbonyl and there is degradation, the beta lactam ring is no longer there

Question 34

What does attaching an electronegative group to the left side chain do?

Answer 34

minimises neighbouring group attack on the beta lactam carbonyl pulls the electrons away from the oxygen

Question 35

Narrow spectrum penicillins?

Answer 35

benzylpenicillin phenoxymethyl penicillin

Question 36

Benzylpenicillin?

Answer 36

does not contain an electronegative group so is very unstable and cannot be given in acidic medium (orally)

Question 37

Phenoxymethyl penicillin?

Answer 37

contains an additional oxygen which is electronegative and is enough to make is less susceptible to degradation can be given orally

Question 38

What are beta lactamases?

Answer 38

proteins which are produced by bacteria in response to being treated with a beta lactam antibiotic

Question 39

What do beta lactamases do?

Answer 39

cleave the beta lactam ring, breaking the bat lactam cycle and make the antibiotic totally inactive

Question 40

What is flucloxacillin?

Answer 40

resistant to beta lactamases

Question 41

Why is flucloxacillin resistant to beta lactamases?

Answer 41

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

Question 42

If flucloxacillin broad or narrow spectrum?

Answer 42

narrow spectrum works very well on gram positive

Question 43

What is flucloxacillin used for?

Answer 43

used as the treatment of choice in staph aureus infections involving skin and soft tissue

Question 44

When is temocillin used?

Answer 44

in the presence of beta lactamases

Question 45

Structure of temocillin?

Answer 45

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

Question 46

What do beta lactamase inhibitors do?

Answer 46

bind covalently to beta lactamases

Question 47

Examples of beta lactamase inhibitors?

Answer 47

clavulanic acid and tazobactam

Question 48

Co-amoxiclav?

Answer 48

Augmentin = amoxicillin + clavulanic acid

Question 49

Tazocin?

Answer 49

Piperacillin + tazobactam

Question 50

What do beta lactamase inhibitors look like?

Answer 50

very similar to beta lactams but do not have the side chain on the left

Question 51

What does ampicillin have?

Answer 51

additional electronegative group (NH2) so it can be taken orally

Question 52

What does amoxicillin have?

Answer 52

Additional electronegative group (NH2) and an additional hydroxyl group

Question 53

Broad spectrum penicillins?

Answer 53

Amipicillin and amoxicillin hydrophilic and have low Mwt so can go through the porins of gram negative

Question 54

Penicillins that work on pseudomonas aeruginosa?

Answer 54

ticarcillin and piperacillin

Question 55

How can ticarcillin and piperacillin be given?

Answer 55

not orally they do not have electronegative groups on the side chains

Question 56

Gram positive active cephalosporins?

Answer 56

cefalexin, cefradine, cefadroxil, defaclor

Question 57

Beta lactamase resistant cephalosporins?

Answer 57

cefuroxime

Question 58

Gram negative active cephalosporins and beta lactamase resistant?

Answer 58

cefotaxime, ceftriaxone, cefixime, cefpodoxime

Question 59

Cephalosporins active against pseudomonas aeruginosa and beta lactamase resistant?

Answer 59

Ceftazidime

Question 60

Natural cephalosporins?

Answer 60

easily degraded

Question 61

Oral (acid stable) cephalosporins?

Answer 61

cefalexin and cefaclor

Question 62

Parenteral cephalosporins?

Answer 62

ceftazidime

Question 63

What does ceftazidime contain?

Answer 63

zwitterion has both charges at physiological pH not easily absorbed through membranes as it is not lipophilic

Question 64

Beta lactamase resistant cephalosporins?

Answer 64

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

Question 65

Anti-pseudonmonal cephalosporins?

Answer 65

ceftazidime has the quaternary ammonium making it active on pseudomonas

Question 66

What are the aims of drug development of penicillins?

Answer 66

Aim 1 - increase stability in acidic medium Aim 2 - resistance to beta lactamases Aim 3 - spectrum of activity