ICL 2.27: Antibiotics II

Question 1

what is the similarity between all B-lactam drugs?

Answer 1

β-Lactams are divided into several classes based on their structure and function; and are often named by their origin, but all classes have a common β-Lactam ring structure

Question 2

what are the components of the penicillin structure?

Answer 2

1. thiazolidine ring
2. β-lactam ring
3. R group

Question 3

how do β-lactam drugs work?

Answer 3

they inhibit cell wall synthesis

they weaken the cell wall and cause pressure inside to build up and the bacterium will eventually explode

the bacterial cell wall is a cross linked polymer called peptidoglycan which allows a bacteria to maintain its shape despite the internal turgor pressure caused by osmotic pressure differences

if the peptidoglycan fails to crosslink the cell wall will lose its strength which results in cell lysis

all β-lactams disrupt the synthesis of the bacterial cell wall by interfering with the transpeptidase which catalyzes the cross linking process

Question 4

do β-lactam drugs work better on gram + or - bacteria?

Answer 4

gram +

the outer membrane of gram - bacteria blocks the B-lactam from getting in and working

instead, with gram - bacteria, they have porins in the outer membrane that allow nutrients to come so we can target these instead to kill the bug

Question 5

what is the structure of peptidoglycan?

Answer 5

peptidoglycan is a carbohydrate composed of alternating units of NAMA and NAGA

Question 6

how does peptidoglycan crosslinking work in gram - vs. gram + bacteria?

Answer 6

the NAMA units have a peptide side chain which can be cross linked from the L-Lys residue to the terminal D-Ala-D-Ala link on a neighboring NAMA unit

this is done directly in gram (-) bacteria and indirectly via a pentaglycine bridge on the L-lysine residue in gram (+) bacteria

Question 7

what does PBP stand for?

Answer 7

penicillin binding protein

Question 8

what is the function of PBPs?

Answer 8

PG cross linking reaction is catalyzed by a class of transpeptidases known as penicillin binding proteins (PBPs)

a critical part of the process is the recognition of the D-Ala-D-Ala sequence of the NAMA peptide side chain by the PBP

interfering with this recognition disrupts the cell wall synthesis

Question 9

how do β-lactams effect PBPs?

Answer 9

PG crosslinking is catalyzed by PBPs

part of that reaction is the recognition of the D-Ala-D-Ala sequence of the NAMA peptide side chain by the PBP

interfering with this recognition disrupts the cell wall synthesis

β-lactams mimic the structure of the D-Ala-D-Ala link and bind to the active site of PBPs, disrupting the cross-linking process

Question 10

what is the biochemistry behind how β-lactams effect PBPs?

Answer 10

the amide of the β-lactam ring is unusually reactive due to ring strain and a conformational arrangement which does not allow the lone pair of the nitrogen to interact with the double bond of the carbonyl

β-Lactams acylate the hydroxyl group on the serine residue of PBP active site in an irreversible manner

the hydroxyl of PBP attacks the amide and forms a tetrahedral intermediate –> the tetrahedral intermediate collapses, the amide bond is broken, and the nitrogen is reduced; PBP is now covalently bound by the drug and cannot perform the cross linking action

this reaction is further aided by the oxyanion hole, which stabilizes the tetrahedral intermediate and thereby reduces the transition state energy

Question 11

are β-lactams drugs bacteriacidal or bacteriastatic?

Answer 11

bacteriacidal

you have a PBP covalently linked to a β-lactams

this irreversible binding to PBPs makes it so that PG can’t crosslink

Question 12

what do different R groups in various β-lactam drugs change?

Answer 12

the MOA for all β-lactam is the same

but something that could be different is the R group

with different R groups you have a different range of activity and the types of bacteria that the drug can target

Question 13

do β-lactam drugs work better on gram + or gram - bacteria?

Answer 13

gram +

β-Lactams can easily penetrate gram (+) bacteria, but the outer cell membrane of gram (-) bacteria prevents diffusion of the drug

β-Lactams can be modified to make use of import porins in the cell membrane

Question 14

what is the range of activity of β-lactam drugs?

Answer 14

work better on gram + bacteria because no outer membrane

β-Lactams also have difficulty penetrating human cell membranes, making them ineffective against atypical bacteria which inhabit human cells

bacteria which lack peptidoglycan in their cell wall will not be affected by β-lactams

Question 15

how are the classes of β-lactams distinguished?

Answer 15

the classes of β-lactams are distinguished by the variation in the ring adjoining the β-lactam ring and the side chain at the α position

Question 16

how does modifying the R group of a β-lactam drug improve it?

Answer 16

β-Lactam type antibiotics can be modified at various positions to improve their ability to:

1. be administered orally (survive acidic conditions)
2. be tolerated by the patient (allergies)
3. penetrate the outer membrane of gram (-) bacteria
4. prevent hydrolysis by β-lactamases
5. acylate the PBPs of resistant species (there are many different PBPs)

Question 17

what are natural penicillins?

Answer 17

natural penicillins are those which can be obtained directly from the penicillium mold and do not require further modification

many species of bacteria are now resistant to these penicillins.

Question 18

which penicillin is a natural penicillin?

Answer 18

penicillin G

Question 19

what are the characteristics of penicillin G?

Answer 19

it’s a natural penicillin = obtained directly from the penicillium mold and do not require further modification

1. it can’t be given orally because it gets degraded in the stomach because the β-lactam ring pops open
2. narrow spectrum of activity = only effects gram + bacteria
3. short half-life

Question 20

if penicillin G only effects gram + bacteria, how is effective against gonorrhea ?

Answer 20

gonorrhea is gram - bacteria but it has a differen structure on its cell wall

Question 21

how do you administer penicillin G?

Answer 21

it’s a natural penicillin

penicillin G can NOT be administered orally due to the acidic conditions of the stomach

Question 22

what’s the difference between penicillin G and penicillin V?

Answer 22

the R group! it’s a phenyl group and bound oxygen

Question 23

how is penicillin V administered?

Answer 23

its R group is a phenyl group and bound oxygen

adding the oxygen decreases the nucleophilicity of the carbonyl group, making penicillin V acid stable and orally viable

this allows for it to be prescribed orally and it won’t be broken down in stomach acid which is great

Question 24

what are the characteristics of penicillin V?

Answer 24

1. can be given orally
2. short half life
3. narrow spectrum of activity

Question 25

how do you increase the half life of penicillin G?

Answer 25

combine with probenicid! this decreases the rate of renal secretion probenecid is a drug that counteracts the anion pump in the kidney that allows rapid excretion of penicillins and ultimately keeps penicillin G in the blood longer

Question 26

what are repository penicillins?

Answer 26

repository penicillins have pretty much replaced use of probenicid repository pens are not soluble, and should only be administered by i.m. since they're not soluble they have really slow absorption! ex. procaine penicillin G ex. benzathine penicillin G

Question 27

what is the function of repository penicillins?

Answer 27

they were developed to prolong duration of penicillin G in the blood

Question 28

what is penicillin G procain?

Answer 28

a type of repository penicillin it last 12-24 hours in the body and is given IM, not IV due do rsik of procaine toxicity but it's seldom used now due to increased frequency of penicillinase producing N. gonorrhea

Question 29

what is penicillin G benzathine?

Answer 29

a type of repository penicillin lasts 3-4 weeks in the body painful at the injection site

Question 30

what is penicillin G benzathine used to treat?

Answer 30

1. syphilis 2. rheumatic fever prophylaxis (inhibits group A beta- hemolytic streptococci) 3. streptococcal pharyngitis

Question 31

what is the issue with pencillin G having a short half life?

Answer 31

if you have such a fast half life, commonly replicating bacteria replicate every 20 minutes so if it’s slower than that and your drug is in and out, it won’t even have time to be effective so when you add the repository penceillin it helps them have more efficacy

Question 32

how have bacteria found ways to become resistant to β-lactams?

Answer 32

1. intrinsic defenses such as efflux pumps can remove the β-lactams from the cell 2. β-Lactamases 3. bacteria may acquire resistance through mutation at the genes which control production of PBPs, altering the active site and binding affinity for the β-lactam

Question 33

what are β-Lactamases?

Answer 33

enzymes which hydrolyze the amide bond of the β-lactam ring, rendering the drug useless

Question 34

what are antistaphylococcal penicillins?

Answer 34

penicillins with bulky R groups penicillins that have bulky side groups can block the β-Lactamases which hydrolyze the lactam ring the R group basically acts like a shield so that β-lactamases proteins can't bind and disable β-lactam ring

Question 35

which bacteria have β-lactamases? what does this do?

Answer 35

1. S. aureus 2. S. epidermidis these bacteria have β-lactamases which makes them resistant to penicillin G and V so we had to develop semi-synthetic penicillins through rational drug design with bulky side groups to inhibit β-lactamases methicillin was the first penicillin developed with this type of modification, and since then all bacteria which are resistant to any type of penicillin are designated as methicillin resistant (MRSA)

Question 36

what does MRSA mean/stand for?

Answer 36

MRSA = methicillin-resistant S. aureus it's just any bacteria that's resistant to any type of penicillin

Question 37

what is methicillin?

Answer 37

a type of penicillin with a bulky R group that is supposed to protect the β-lactam ring from bacterial β-lactamase it's acid sensitive though so it's given IV, not orally

Question 38

which drugs are methicillin derivatives?

Answer 38

1. oxacillin 2. nafcillin methicillin is acid sensitive and has been improved upon by adding electron withdrawing groups, resulting in *orally viable* drugs such as oxacillin and nafcillin

Question 39

which drugs are antistaphylococcal penicillins?

Answer 39

1. methicillin 2. nafcillin 3. oxacillin

Question 40

what's the problem with antistaphylococcal penicillin drugs?

Answer 40

due to the bulky side group, all of the antistaphylococcal drugs have difficulty penetrating the cell membrane and are less effective than other penicillins

Question 41

what's the problem with methicillin?

Answer 41

no longer marketed because of renal toxicity (interstitial nephritis)

Question 42

why is nafcillin better than methicillin?

Answer 42

methicillin causes renal toxicity nefcillin on the otherhand is eliminated by biliary excretion = less chance of CNS toxicity in patients with compromised renal function

Question 43

what are aminopenicillins?

Answer 43

penicillins with hydrophilic groups in order to increase the range of activity, the penicillin has been modified to have more hydrophilic groups, allowing the drug to penetrate into Gram (-) bacteria via the porins

Question 44

which drugs are aminopenicillins?

Answer 44

1. ampicillin R = Ph 2. amoxicillin R = Ph-OH

Question 45

how is amoxicillin given?

Answer 45

amoxicillin is better absorbed orally and can be given with meals it causes less GI disturbance

Question 46

what are the pros and cons of aminopenicillins?

Answer 46

these penicillins have a wider range of activity than natural or antistaphylococcal drugs, but without the bulky side groups are once again susceptible to attack by β-lactamases

Question 47

how can you modify aminopenicillins to make them better?

Answer 47

due to the effectiveness of the aminopenicillins, a second modification is made to the drug at the carboxyl group changing the carboxyl group to an ester allows the drug to penetrate the gut wall where it is later hydrolyzed into the more polar active form by esterase enzymes this has greatly expanded the oral availability of the aminopenicillin class

Question 48

what are extended spectrum penicillins?

Answer 48

extended spectrum penicillins are similar to the aminopenicillins in structure but have either a carboxyl group or urea group instead of the amine 1. carboxypenicillins 2. ureidopenicillins like the aminopenicillins the extended spectrum drugs have an increased activity against Gram (-) bacteria by import of porins however, they are more effective than the aminopenicillins and not as susceptible to β-lactamases

Question 49

which drugs are carboxypenicillins?

Answer 49

1. ticarcillin 2. carbenicillin * extended spectrum penicillins

Question 50

which drugs are ureidopenicillins?

Answer 50

1. azlocillin 2. mezlocillin 3. piperacillin * extended spectrum penicillins

Question 51

how are extended spectrum penicillins administered?

Answer 51

these drugs also have difficulty penetrating the gut wall and must be administered intravenously if not available as a prodrug

Question 52

how toxic are β-lactams?

Answer 52

they're not really! β-lactams target PBPs exclusively, and because human cell membranes do not have this type of protein β-lactams are relatively non toxic compared to other drugs which target common structures such as ribosomes

Question 53

what are the different types of β-lactams?

Answer 53

1. natural penicillins 2. repository penicillins 3. antistaphylococcal penicillins 4. aminopenicillins 5. extended spectrum penicillins

Question 54

which β-lactams are natural penicillins?

Answer 54

1. penicillin G | 2. penicillin V

Question 55

which pencillins are repository penicillins?

Answer 55

1. Penicillin G procaine | 2. Penicillin G benzathine

Question 56

what are the side effects of penicillin?

Answer 56

1. hypersensitivity 2. neurotoxicity 3. cation toxicity 4. fluid and electrolyte loss 5. herxheimer reaction 6. Coombs-positive hemolytic anemia 7. interstial nephritis 8. diarrhea, pseudomembranous colitis, maculopapular rash 9. prolonged bleeding

Question 57

how can penicillin cause hypersensitivity?

Answer 57

type II hypersensitivity reaction usually rash or serum sickness 10% of people are allergic to penicillin

Question 58

how can penicillin cause neurotoxicity?

Answer 58

seizures or coma associated with high doses of any penicillin (e.g., 60 g/day, i.v.)

Question 59

how can penicillin cause cation toxicity?

Answer 59

penicillins are administered as Na+ or K+ salts so sometimes there's a buildup

Question 60

how can penicillin cause fluid and electrolyte loss?

Answer 60

high doses of any penicillin: penicillin anion is concentrated in renal tubules and produces an osmotic diuresis: increases Na+ uptake by principal cells of collecting tubules & secretion of K+ and H+ into the luminal fluid thereby producing hypokalemic alkalosis

Question 61

what is the herxheimer reaction?

Answer 61

a side effect of penicillin chills, fever, headache, muscle & joint pain shortly after first penicillin injection in patients with syphilis rash develops at syphilitic lesions – disappears in a few weeks does not recur with subsequent penicillin injections usually not necessary to withhold treatment

Question 62

how can penicillin cause Coombs-positive hemolytic anemia?

Answer 62

a condition of low red blood cell count caused by immune system lysis resulting in RBC destruction. penicillin dose > 6 grams/day about 10% of patients will show a positive direct Coombs test --> the Direct Coombs test is used for autoimmune hemolytic anemia a few patients will become anemic

Question 63

how can penicillin cause interstitial nephritis?

Answer 63

this is the reason methicillin was withdrawn from the market but it can be seen with other penicillins too at dosages >10 g/day!!

Question 64

which penicillin drugs cause diarrhea, pseudomembranous colitis, and maculopapular rash?

Answer 64

1. amoxicillin 2. ampicillin maculopapular rash is especially prevalent in patients with mononucleosis

Question 65

which penicillin drugs cause prolonged bleeding?

Answer 65

1. carbenicillin 2. ticarcillin they inhibit platelet aggregation!

Question 66

what is the overview characteristics of the β-lactam ring?

Answer 66

1. essential for antimic activity; it's the target of bacterial β-lactamases 2. responsible for drug allergy 3. responsible for neurotoxicity

Question 67

what are the characteristics of the weak acid COO- group in penicillin structure?

Answer 67

1. renal tubular secretion | 2. potential cation toxicity