ICL 2.27: Antibiotics II Flashcards
what is the similarity between all B-lactam drugs?
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
what are the components of the penicillin structure?
- thiazolidine ring
- β-lactam ring
- R group
how do β-lactam drugs work?
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
do β-lactam drugs work better on gram + or - bacteria?
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
what is the structure of peptidoglycan?
peptidoglycan is a carbohydrate composed of alternating units of NAMA and NAGA
how does peptidoglycan crosslinking work in gram - vs. gram + bacteria?
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
what does PBP stand for?
penicillin binding protein
what is the function of PBPs?
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
how do β-lactams effect PBPs?
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
what is the biochemistry behind how β-lactams effect PBPs?
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
are β-lactams drugs bacteriacidal or bacteriastatic?
bacteriacidal
you have a PBP covalently linked to a β-lactams
this irreversible binding to PBPs makes it so that PG can’t crosslink
what do different R groups in various β-lactam drugs change?
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
do β-lactam drugs work better on gram + or gram - bacteria?
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
what is the range of activity of β-lactam drugs?
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
how are the classes of β-lactams distinguished?
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
how does modifying the R group of a β-lactam drug improve it?
β-Lactam type antibiotics can be modified at various positions to improve their ability to:
- be administered orally (survive acidic conditions)
- be tolerated by the patient (allergies)
- penetrate the outer membrane of gram (-) bacteria
- prevent hydrolysis by β-lactamases
- acylate the PBPs of resistant species (there are many different PBPs)
what are natural penicillins?
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.
which penicillin is a natural penicillin?
penicillin G
what are the characteristics of penicillin G?
it’s a natural penicillin = obtained directly from the penicillium mold and do not require further modification
- it can’t be given orally because it gets degraded in the stomach because the β-lactam ring pops open
- narrow spectrum of activity = only effects gram + bacteria
- short half-life
if penicillin G only effects gram + bacteria, how is effective against gonorrhea ?
gonorrhea is gram - bacteria but it has a differen structure on its cell wall
how do you administer penicillin G?
it’s a natural penicillin
penicillin G can NOT be administered orally due to the acidic conditions of the stomach
what’s the difference between penicillin G and penicillin V?
the R group! it’s a phenyl group and bound oxygen
how is penicillin V administered?
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
what are the characteristics of penicillin V?
- can be given orally
- short half life
- narrow spectrum of activity
how do you increase the half life of penicillin G?
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
what are repository penicillins?
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
what is the function of repository penicillins?
they were developed to prolong duration of penicillin G in the blood
what is penicillin G procain?
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
what is penicillin G benzathine?
a type of repository penicillin
lasts 3-4 weeks in the body
painful at the injection site
what is penicillin G benzathine used to treat?
- syphilis
- rheumatic fever prophylaxis (inhibits group A beta- hemolytic streptococci)
- streptococcal pharyngitis
what is the issue with pencillin G having a short half life?
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
how have bacteria found ways to become resistant to β-lactams?
- intrinsic defenses such as efflux pumps can remove the β-lactams from the cell
- β-Lactamases
- 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
what are β-Lactamases?
enzymes which hydrolyze the amide bond of the β-lactam ring, rendering the drug useless
what are antistaphylococcal penicillins?
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
which bacteria have β-lactamases? what does this do?
- S. aureus
- 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)
what does MRSA mean/stand for?
MRSA = methicillin-resistant S. aureus
it’s just any bacteria that’s resistant to any type of penicillin
what is methicillin?
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
which drugs are methicillin derivatives?
- oxacillin
- 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
which drugs are antistaphylococcal penicillins?
- methicillin
- nafcillin
- oxacillin
what’s the problem with antistaphylococcal penicillin drugs?
due to the bulky side group, all of the antistaphylococcal drugs have difficulty penetrating the cell membrane and are less effective than other penicillins
what’s the problem with methicillin?
no longer marketed because of renal toxicity (interstitial nephritis)
why is nafcillin better than methicillin?
methicillin causes renal toxicity
nefcillin on the otherhand is eliminated by biliary excretion = less chance of CNS toxicity in patients with compromised renal function
what are aminopenicillins?
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
which drugs are aminopenicillins?
- ampicillin
R = Ph
- amoxicillin
R = Ph-OH
how is amoxicillin given?
amoxicillin is better absorbed orally and can be given with meals
it causes less GI disturbance
what are the pros and cons of aminopenicillins?
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
how can you modify aminopenicillins to make them better?
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
what are extended spectrum penicillins?
extended spectrum penicillins are similar to the aminopenicillins in structure but have either a carboxyl group or urea group instead of the amine
- carboxypenicillins
- 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
which drugs are carboxypenicillins?
- ticarcillin
- carbenicillin
* extended spectrum penicillins
which drugs are ureidopenicillins?
- azlocillin
- mezlocillin
- piperacillin
* extended spectrum penicillins
how are extended spectrum penicillins administered?
these drugs also have difficulty penetrating the gut wall and must be administered intravenously if not available as a prodrug
how toxic are β-lactams?
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
what are the different types of β-lactams?
- natural penicillins
- repository penicillins
- antistaphylococcal penicillins
- aminopenicillins
- extended spectrum penicillins
which β-lactams are natural penicillins?
- penicillin G
2. penicillin V
which pencillins are repository penicillins?
- Penicillin G procaine
2. Penicillin G benzathine
what are the side effects of penicillin?
- hypersensitivity
- neurotoxicity
- cation toxicity
- fluid and electrolyte loss
- herxheimer reaction
- Coombs-positive hemolytic anemia
- interstial nephritis
- diarrhea, pseudomembranous colitis, maculopapular rash
- prolonged bleeding
how can penicillin cause hypersensitivity?
type II hypersensitivity reaction
usually rash or serum sickness
10% of people are allergic to penicillin
how can penicillin cause neurotoxicity?
seizures or coma
associated with high doses of any penicillin (e.g., 60 g/day, i.v.)
how can penicillin cause cation toxicity?
penicillins are administered as Na+ or K+ salts so sometimes there’s a buildup
how can penicillin cause fluid and electrolyte loss?
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
what is the herxheimer reaction?
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
how can penicillin cause Coombs-positive hemolytic anemia?
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
how can penicillin cause interstitial nephritis?
this is the reason methicillin was withdrawn from the market but it can be seen with other penicillins too at dosages >10 g/day!!
which penicillin drugs cause diarrhea, pseudomembranous colitis, and maculopapular rash?
- amoxicillin
- ampicillin
maculopapular rash is especially prevalent in patients with mononucleosis
which penicillin drugs cause prolonged bleeding?
- carbenicillin
- ticarcillin
they inhibit platelet aggregation!
what is the overview characteristics of the β-lactam ring?
- essential for antimic activity; it’s the target of bacterial β-lactamases
- responsible for drug allergy
- responsible for neurotoxicity
what are the characteristics of the weak acid COO- group in penicillin structure?
- renal tubular secretion
2. potential cation toxicity
