Unit 2 Flashcards
Gram (+) vs Gram (-):
-Outer membrane
-B-lactamases
-Peptidoglycan
-AA residues
-Cross-linking
Outer membrane:
(+) - drugs can penetrate outer layers of cell wall, membrane blocks drugs, one membrane
(-) - Some drugs can get through porins of outer membrane, two membranes
B-lactamases:
(+) - Excreted through cell wall to outer membrane, requires more to be functional
(-) - Confined to periplasmic space
Peptidoglycan
(+) - thicker than (-)
AA residues:
Both have G/M alternating saccharides
(+) - Lysine residues
(-) - DAP
Crosslinking:
(+) - Bridge between L-lys strand and terminal of D-ala of 2nd molecule
(-) - Bridge between DAP residue of one strand and terminal D-ala
Transpeptidase mechanism
Serine hydroxyl group hits the amide linkage
Tetrahedral intermediate forms, D-ala residue eliminated
New peptidoglycan binds H2N to carbonyl of existing strand
Transpeptidase unbinds
Beta-lactam mechanism
Two factors for reactivity
Reason for varying responses to B-lactams
Why they do not react with host-cell proteins
BL mimics D-Ala group that transpeptidase wants to bind to and forms inactivated enzyme, and defective cell wall is the result
Highly strained 4 member ring with 90 angle N-C-C bond
Turning this carbonyl into a tetrahedral carbon changes it to a more relaxed 109
Steric inhibition by the non-bonded electrons in nearby nitrogen group makes it act as more of a ketone carbonyl than an amide
Different penicillin binding proteins
Bacteria have very unnatural D-ala residues
Non beta-lactamase forms of resistance to beta-lactams
Mechanism of B-lactamase
Decreased drug uptake
Mutation of PBP
Efflux pump
Hydrolysis of the B-lactam ring
Allergenicity of B-lactam rings:
-Mechanism
-Can it be modified?
Binds to host protein
No- caused by common pharmacologic portion of drug
Penicillin degradation mechanism (acidic condition)
Basic
H+ attacks carbonyl carbon. If the R group is more electronegative then the penicillin will be more stable in the acid
Other carbonyl carbon gets attacked by OH group
Protein binding:
-Penicillin with more _____ side chain will be more protein bound
-Protein binding reduces ______, does not change ______
-Protein binding protects from _____
Lipophilic
Bioavailability, t1/2
Degradation
Excretion
-How does the renal excretion
-Drug used to prolong half life of _____ penicillin
10% glomerular filtration
90% tubular secretion
-t1/2 increased for kidney disease
Two mechanisms, one for cation and one for anion
Can also be hepatically excreted
Anionic, Probenecid
PK:
-Desired concentration
-Where penicillins do not distribute
-Half lives of most penicillin
-Which drug is excreted hepatically
4-5x MIC. 2 ug/mL or higher, peak at 8-25
CSF, unless parenteral
0.5-2h
Nafcillin
Benzylpenicillin (Penicillin G):
-Structure
-Sensitivity to BL
-Administration
-Toxicity
-Spectrum
Has benzyl ring
Yes
Orally, but better parenterally
Acute allergic reactions
Gram (+) cocci plus Neisseria gonorrhoeae/hamophilus influenzae (both -)
Benzylpenicillin benzathine and benzylpenicillin procaine
-Mechanism
-Risk
-Mod/Severe
Lower solubility, releases slower from the IM injection site
IV can cause cardiac arrest
Moderately severe infections of upper respiratory tract, scarlet fever, skin/soft tissue
Streptococci/Pneumococci
Phenoxymethoxyl (Penicillin V)
-More stable in ____
-Structure that makes it more stable
-Spectrum of activity
-A bit less sensitive to ____
Acid/Stomach
Ether before the benzyl ring
Same as Pen G
BL
Methicillin:
-BL sensitivity and reason
-Route of administration and reason
-Spectrum
No
Steric inhibition via the phenyl ring on amide carbonyl
Removal
Injection, unstable to stomach acid due to electron donation by amide carbonyl increasing nucleophilicity
Narrow, too much resistance now
MRSA due to mutation in PBP, mecA gene produces PBP2A
Nafcillin:
-Structure
-Sensitivity
-Comparison to methicillin
Double ring R group
Not BL sensitive
Clinically identical, more stable in stomach acid
Oxacillin:
-Structure
-BL sensitivity
-Spectrum
Long chain with ring at end, chain can flip
No
Staphylococcus/Streptococcus
-Used for penicillin resistant staph aureus
The three BL resistant oral penicillins:
-Names
-Four points to know
All isoxazoles: Oxacillin, Cloxacillin, Dicloxacillin
Less potent against gram + that do not produce BL
Highly protein bound
Cross resistant with methicillin
Dicloxacillin the only one still used
BL resistant, broad spectrum, oral penicillins
-Drugs
-Spectrum
-Special structure
Ampicillin
Amoxicillin
Many gram - bacteria sensitive to this
NH2 group is protonated 50% at physiological pH, will increase polarity and allow better entrance through porins
Ampicillins have OH group on aromatic ring
Beta-lactamase inhibitors
Used in combination with B-lactamase sensitive penicillins
Acylate the serine hydroxyl group in the active site of beta-lactamase
Amox/clav - augmentin
Sulbactam/Ampicillin- Unasyn
Tazobactam/Piperacillin- Zosyn
Avibactam/Ceftazidine
What are cephalosporins synthesized from?
7-aminocephalosporanic acid
What adds to the mechanism of cephalosporin?
Leaving group that facilitates ring opening
MOA of cephalosporin resistance
Hydrolyzed by B-lactamases
If X group is electron attracting, it will make beta-lactamase more reactive
Allergenicity of cephalosporins
Should be used with caution, if at all, with penicillin allergies
Fever and rashes
Classification of cephalosporins
-Trend
Increased gram (-) coverage and decreased gram (+) coverage
First generation
-Activity
-Structure of oral vs parenteral
Gram +
Substituents at C-3 for oral are not chemically reactive
Second generation cephalosporins
-Activity
-Features (4)
Retain G+ activity, and add some G-
Carbamate side chain is less reactive towards hydrolysis with the electron donating NH
Oxime ether increases resistance to hydrolysis, syn is more resistant
Cefuroxime penetrates BBB
Prodrug of cefuroxime is available
Third generation cephalosporins
-Activity
-Features
Big increase in G+
-Nearly all of them have an aminothiazole substituent with oxime at position 7 which is good for B-lactamases
-Charged pyridinium ring at C-3 is very good leaving group which activates the B-lactam ring
-Side chain carboxyl helps take out G-
Fourth generation cephalosporins
-Activity
-Features
Retain spectrum of third gen, add in some that are resistant to gen3
They are also more active against gram+
Syn methoximino group at c7 reduces resistance on cefepime
N-methylpyrrolidine moiety is good leaving group and increase reactivity of B-lactam
Fifth generation cephalosporins
Carbapenems
-Original molecule too reactive to be used clinically (derivative of this drug that is used)
-Structural feature
Thienamycin: primary amino group attacks B-lactam ring, imipenem
Like penicillin, but sulfur group that is present on thiazoldine ring is replaced by methylene, greater ring strain
Imipenem:
-What it inhibits
-What hydrolyzes this and how is is overcome?
-Dosage form
B-lactamases
Renal dihydropeptidase, cilastatin
Parenteral
Meropenem:
-more highly resistant to _____
-Can be administered without _____
-Can be combined with ______ for complicated UTIs
Beta lactamases
Cilastatin
Vaborbactam
Ertapenem has less ________ but has _____
Broad spectrum
Longer half-life
Monobactam
-Drug
-Relevant group
-Spectrum
-Features (3)
Aztreonam (completely synthetic)
Sulfamic acid end taking place of C2 carboxyl group
Mostly severe G- infections
Electronegative sulfamic acid activates the B-lactam ring
No reported ross-allergenicity with penicillins or cephalosporins
Oxime ether increase resistance to B-lactamases
Two glycopeptides
Vancomycin
Teicoplanin
Vancomycin:
-MOA
-MIC required to be considered susceptible
-Resistance
Mechanism of vanc resistance
How is vanc eliminated
Vanc can be synergistically combined with
Inhibitor of Gram + cell wall biosynthesis
Steric hinderance by binding over the D-ala-D-ala end
4
usually last line of defense for multidrug resistant bacteria. Europe has showed som
D-ala-lactate mutation, vanc has much less affinity
90% by kidneys
Gentamicin
Aminoglycosides bind to _____ causing a ____ mutation
30S ribosomal subunit
Frameshift
Toxicities of aminoglycosides
Ototoxic (irreversible)
Nephrotoxic (reversible, more frequent if also taking loop diuretics)
Three resistance mechanisms to AGS
Inactivation by acetylation, adenylation, phosphorylation
Altered ribosomes
Altered AGS uptake (goes away after drug is removed
Penicillins/aminoglycosides used for _____
Streptomycin used for _______*
______ has retained antibiotic activity against hospital AGS resistant infections
Bacterial endocarditis
TB (only in combination)
Amikacin
Amikacin
Tobramycin
Gentamicin used for ______
Orally used AGS
Streptomycin is used for _____ with _____
Joint/bone G- infections, also can be used topically, eye infections as well
Neomycin B/Paromomycin
TB, other antibiotics
Macrolide abx structure
14-membered lactone rings with alternating methyl groups
Formed by acyl-carrier protein, via polyketide pathway
Desosamine and cladinose sugars are attached to ring
pKa is 8.8, can form salts (Glucoheptonic and lactobionic) that are more soluble
How do macrolides work
Bind reversibly to the P site so the tRNA transfer cannot happen- involving 23S RNA
Four mechanisms of resistance from macrolides
Lactone ester hydrolase induced hydrolyze macrolide
Drug induced production of RNA methylase that methylates part of 23S RNA on the 50S ribosome inhibiting the macrolide binding
Mutation of adenine to guanine at A2058, reduction in affinity to binding
Efflux pump
______ inactivates erythromycin, this can be prevented with ______
Stable formulations
OH groups affected in acidic conditions, enteric coated formulation
6-OCH: clarithromycin
Amine analog: Azithromycin
Erythromycin metabolism
Interaction, which drugs
Side effects
Demethylation in the liver
Inhibit CYP3A and other P450 enzymes, with erythromycin and clarithromycin
GI, allergies, jaundice, stenosis
