Antibiotics 1 - Cell wall and Beta Lactams Flashcards by Chris Rodarte

Main barrier keeping drugs out of cell in gram positive

Bacterial membrane

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Gram positives excrete…

B lactamase through the cell wall into the external environment

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Outer membrane barrier property in gram negative?

excludes drugs, but some may stil get in through porins in the OUTER cell membrane

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In gram negatives, where is the beta lactamase located?

in the periplasmic space

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type with thicker PG

gram positive

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Gram negatives have an ____ that contains ____ which may facilitate entry

outer membrane

porins

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G- Peptidoglycan contains _______

meso-diaminopimelic acid residue

(DAP)

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G+ peptidoglycan contains ____ instead of the ____ that gram negative contains

L-Lysine

DAP

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Crosslinking occurs in G- between the ___ and ____

DAP and D-ala

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G+ crosslinking occurs between…

L-Lys and terminal D-ala

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S. aureus crosslink composition

5 glycine residues

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Transpeptidase mechanism:

The OH from ___ attacks the ___ carbon of peptide-d-ala-d-ala

OH from Transpeptidase attacks the amide carbon

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Transpeptidase mechanism: ____ is formed as an intermediate which is more reactive

Ester linkage

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After the ester linkage is broken, a ____ intermediate is formed.

tetrahedral

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Final products of transpeptidase mechanism

Peptide- D-Ala-Gly-Gly -Peptide

Transpeptidase

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B-lactam MOA

acylates the transpeptidase’s serine residue in the enzyme active site.

–> inactivates the enzymes and inhibits cross linking.

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reactivity of B lactam system is due to…

highly strained 4-membered ring

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NCC bind of the B lactam is compressed to ___ from _____

compressed to 90 from normal 120 angle

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Bond angle of a tetrahedral carbon

109

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Stress can be releived in beta lactam strain by conversion of…

carbonyl to the tetrahydral intermediate

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The beta lactal carbonyl is more reactive because…

its more like a ketone carbonyl than an amide carbonyl, because of the steric inhibition of overlap of the non-bonded electrons of the nitrogen with the adjacent carbonyl.

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Penicillins assume a _____ structure with _____

folded ring structure with an sp3 hybridized nitrogen

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There are many ____ which explains the heterogenecity of bacterial responses

penicillin binding proteins

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The bacterial transpeptidases do not catalyze rxns with host cell proteins because…

the bacterial substrate contains unnatural D-ala residues that arent found in host cell proteins

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Four mechanisms of resistance to beta-lactam

decreased cellular uptake mutation of the PBPs Presence of efflux pump \*\*Induction/elaboration of **B-lactamases**\*\*

Four steps in B lactamase mechanism

[B lactamase + Penicillin] --\> Tetrahedral intermediate --\> Acylated B lactamase --\> [Regenerated enzyme + hydrolyzed penicillin]

Fast step in beta lactamase mechanism =

Hydrolysis of the acylated B-lactamase intermediate

\_\_% of population has beta-lactam AB's

6-8%

How are beta lactams allergenic?

Drug acts as hapten - **acylates host cell proteins** (generates covalent products that are "foreign")

Why can't the allergic reaction of beta lactam be overcome via structural manipulation of the compound?

the reaction originates from the **pharmacore** of the drug

Can you use other penicillin-type drug on a penicillin-allergic person?

NO!

\_\_\_\_ tests for beta lactam allergy are recommended if there is doubt about allergy

Topical flare and wheal test

Main degradation products of Pen G

1. Benzylpenicillenic acid 2. Benzylpenicillic acid 3. Benzylpenicilloic acid

Penicillin hydrolysis products have no \_\_\_\_\_\_\_

antibiotic activity

Hydrolysis of B lactam is \_\_\_

irreversible | (once the ring is opened, no closure)

Electronegative substituents have what effect when they're on the side chain carbonyl?

They r**educe the nucleophilicity** of the side chain amide carbonyl oxygen atom. * Stabilizes the penicillin against hydrolysis under acidic conditions * Increases oral bioavailability

Which is more stable, Pen G or Pen V?

Pen V is more stable to acid hydrolysis \*because the electronegativity of the ether oxygen *decreases the nucleophilicity* of the amide carbonyl

Solutions of penicillins should be used promptly and stored how?

In refrigerator at **pH 6.0-6.8**

\_\_\_\_\_ catalyze penicillin degradation

heavy metal ions

Penicillins with ______ are more highly protein bound

lipophilic side chains

Protein binding effects (2)

1. Reduces BA 2. Protects from degradation

Why isn't half life affected by protein binding?

dissociation rates from protein are fast, and the **renal excretion rates are the rate-limiting factor**

Highest and lowest penicillins protein bound

cloxacillin = \>90% protein bound Ampicillin = 25-30% protein bound

Penicillin excretion routes

renal biliary

Glomerular vs tubular filtration of penicillins

10% glomerular 90% Tubular

Effect of kidney disease on half life of penicillin

prolonged half life

Two mechanisms for tubular excretion

anionic cationinc

Penicillins are anionic or cationic?

anionic. Competition with **probenecid** (anion) for secretion when coadministered with penicillin

_Pen G_ 1. a.k.a 2. Spectrum 3. Beta-lactamase sensitivity? 4. Toxicity

1. Benzylpenicillin 2. Gram+ and *N.gonorrhoeae* and *H. influenzae* 3. Yes, sensitive 4. Acute allergy

Methicillin has no beta lactamase sensitivity because

steric hindrance of nucleophilic attack by the enzyme on the beta lactam carbonyl. _methoxy groups are attached ortho_ to the amide--hinder nucleophilic attack on the lactam.

Why must methicillin be injected?

Electron donation to the amide carbonyl oxygen by the methoxy groups = amide carbonyl oxygen *more nucleophilic* = unstable in acidic conditions

Methicillin is mainly used for

B-lactamase producing S. Aureus

Methicillin is an effective...

inducer of beta lactamase

What causes MRSA to be methicillin resistant

**mutation in mecA** in the penicillin binding protein gene (the protein is **PBP2'**)

Cephapirin is a ___ AB Structural difference?

_cephalosporin_ has a **6-membered sulfur containing ring** instead of a 5 membered ring. Some have an **acetate in the 3 position** = inactivated by hydrolysis by **esterases** (produces hydroxymethyl acid)

Ceph's MOA vs Pen MOA

same

Carbapenems are \_\_\_\_\_\_

carbon analogs of penicillins

Carbapenems have a ____ group instead of ____ that is present in penicillin's thiazolidine ring

methylene sulfur

What does ring strain have to do with sulfur and carbapenems?

The methylene in Carbapenems instead of the sulfur causes increased ring strain because the methylene is smaller

2 things imipenem reacts with

PBP's beta lactamases (inhibits them)

imipenem is hydrolyzed by \_\_\_\_\_ But this can be overcome by \_\_\_\_\_\_\_\_\_\_\_

dehydropeptidase-1 coadministration of **cilastatin** (dehydropeptidase-1 inhibitor)

Imipenem and cilastatin is special because... (2)

it has broader spec than any other AB available active against both gram + and -

imipenem and cilastatin are used to treat

Infections of: **GI, GU, Bone, Skin,** and **Endocardium**

ROA for imipenem-cilastatin

parenterally

Aztreonam disodium is a ____ drug that is inspired by \_\_\_\_\_

totally synthetic monobactams

In Aztreonam, a _______ group takes the place of the c2 carboxyl group (as in pen/ceph)

sulfamic acid

Spectrum of Aztreonam

Almost all gram-

What (Aztreonam) property activates the beta lactam ring to hydrolysis and to reaction with PBP's?

The electronegativity of the sulfamic acid

Aztreonam is used to treat...

severe Gram- infections, especially those by penicillin-resistant organisms acquired in hospitals

Example of cross reactivity between pen and cephs

Ceftazidime | (has identical sidechain)