Antibiotics Inhibiting Cell Wall Biosynthesis

Flashcards covering the medicinal chemistry of cell wall biosynthesis inhibitors, specifically penicillins, cephalosporins, and related molecules.

$\beta$-lactam

A four-membered ring amide with a nitrogen atom at the $\beta$ position to the carbonyl.

Penicillin nucleus

A highly strained bicyclic structure composed of a four-membered lactam ring fused to a five-membered thiazolidine ring.

Cephalosporin nucleus

A bicyclic structure containing a four-membered $\beta$-lactam ring fused to a six-membered dihydrothiazine ring.

6-aminopenicillinic acid (6-APA)

A biosynthetic intermediate isolated by Beecham used as a starting material for the synthesis of most semisynthetic penicillins.

Transpeptidase

An enzyme necessary for the cross-linkage of bacterial cell wall peptidoglycan that contains a serine residue in its active site.

Selective Toxicity (Penicillin)

Explained by penicillin mimicking the structure of $D-ala-D-ala$, which is not present in humans (only $L$-amino acids), and targeting peptidoglycan biosynthesis unique to bacteria.

Absolute Stereochemistry of Penicillins

Designated as $3S:5R:6R$.

Acid Sensitivity factors of Penicillin G

Caused by high ring strain, a highly reactive $\beta$-lactam carbonyl group, and the self-destructive mechanism of the acyl side chain.

Penillic acid and Penicillenic acid

The final products formed from the acid-catalyzed degradation and rearrangement of penicillin G.

Acid Resistant Penicillins

Penicillins modified by adding an electron withdrawing group (EWG) such as amino or halogen to the acyl group to reduce nucleophilicity of the carbonyl oxygen.

$\beta$-lactamase (Penicillinase)

A mutated version of transpeptidase produced by resistant bacteria, such as $S. aureus$, that hydrolyzes the $\beta$-lactam ring.

Steric Shield

The addition of a bulky group to the acyl side chain, such as ortho-substituted phenyl or naphthyl rings, to interfere with $\beta$-lactamase attachment.

Isoxazoyl Penicillins

A class including Oxacillin, Cloxacillin, and Flucloxacillin that is effective against $\beta$-lactamase producing strains and is acid-stable.

Broad Spectrum Penicillins

Penicillins like ampicillin and amoxicillin that have a hydrophilic group at the $\alpha$-carbon, allowing them to pass through bacterial porins.

Ureidopenicillins

Urea-containing penicillins used parenterally for Gram-negative infections like $P. aeruginosa$; they mimic peptidoglycan structures.

Carboxypenicillins

Penicillins like Carbenicillin that contain a carboxylic acid at the $\alpha$-carbon, providing a wider spectrum against Gram-negative strains.

Cephem nucleus

The bicyclic system found in active cephalosporins characterized by a double bond between $C3$ and $C4$.

Cephalosporin C

The first discovered agent of its class, obtained from the fungus Cephalosporium species, with 1/1000 the activity of penicillin G.

1st Generation Cephalosporins

Cephalosporins like Cephalothin and Cephaloridine that have a broader spectrum than penicillin but are still susceptible to $\beta$-lactamase.

Cephalomycins

A type of 2nd generation cephalosporin containing a methoxy group at $C7$, making them active against resistant strains.

3rd Generation Cephalosporins

Cephalosporins featuring an aminothiazole ring which enhances penetration of Gram-negative outer membranes and increases affinity for transpeptidase.

4th Generation Cephalosporins

Zwitterionic oximinocephalosporins with a positively charged leaving group at $C3$, offering better penetration and stability against $\beta$-lactamase.

5th Generation Cephalosporins

IV-administered agents active against methicillin-resistant $S. aureus$ (MRSA) and penicillin-resistant $S. pneumoniae$.

Class I $\beta$-lactamase Inhibitors

Inhibitors like clavulanic acid and sulbactam that possess a heteroatom leaving group at position 1 and cause prolonged enzyme inactivation.

Clavulanic acid

A natural product from Streptomyces with a 1-oxapenam structure that irreversibly inhibits $\beta$-lactamase; used in combination with amoxicillin as Augmentin®.

Carbapenems

Broad-spectrum antibiotics like imipenem and meropenem that lack a thiazolidine or dihydrothiazine ring and possess twice-strained rings.

Monobactams

Monocyclic $\beta$-lactam antibiotics like Aztreonam that have limited activity against Gram-positive bacteria and are highly polar.