Cell Wall/Membrane Acting Agents Part 2

What is the basic structure of penicillins?

β-lactam fused to a 5-membered thiazolidine ring.

What functional group in penicillins mimics terminal D-Ala-D-Ala?

A free COOH group.

Why is stereochemistry important in penicillins?

Penicillins have three asymmetric centers, and absolute stereochemistry must be preserved for activity.

What modification improves β-lactamase resistance in penicillins?

Substitution of the 6-amino group with a bulky aromatic acyl group.

What causes β-lactams to be unstable to nucleophiles?

Hydrolysis by nucleophiles like OH⁻ or β-lactamase, converting penicillin to inactive penicilloic acid.

What is the best pH for β-lactam stability?

pH 6.0–7.2.

Why are β-lactams unstable in acidic conditions?

Acid hydrolysis leads to the opening of the β-lactam ring and inactivation.

How are penicillins made more acid-stable?

Substituting the side chain R with an electron-withdrawing group protects the β-lactam ring from acid degradation.

Why are acid-stable penicillins significant?

They can survive passage through the stomach and be given orally.

What is the structure of cephalosporins?

β-lactam fused to a 6-membered dihydrothiazine ring with a free COOH group.

What is the importance of the 6α hydrogen in cephalosporins?

It is essential for biological activity.

How is β-lactamase resistance improved in cephalosporins?

Addition of an oxime (O-substituted) to the acyl side chain.

What leads to losses in antibiotic activity in cephalosporins?

Isomerization of the olefinic linkage from C-2,3 to C-3,4.

What was the first cephalosporin discovered?

Cephalosporin C, which had activity against some bacterial cultures.

What are the common 1st generation cephalosporins?

Cefazolin, cephalexin, and cefadroxil.

Which 1st generation cephalosporin is used as a parenteral agent?

Cefazolin.

Which 1st generation cephalosporins are oral agents?

Cephalexin and cefadroxil.

What are the common 2nd generation cephalosporins?

Cefuroxime, cefoxitin, cefotetan, and cefuroxime axetil.

Which 2nd generation cephalosporins are parenteral agents?

Cefuroxime, cefoxitin, and cefotetan.

Which 2nd generation cephalosporin is an oral agent?

Cefuroxime axetil.

What are the common 3rd generation cephalosporins?

Ceftriaxone, ceftazidime, ceftazidime/avibactam, ceftolozane/tazobactam, cefpodoxime proxetil, and cefdinir.

Which 3rd generation cephalosporins are parenteral agents?

Ceftriaxone, ceftazidime, ceftazidime/avibactam, and ceftolozane/tazobactam.

Which 3rd generation cephalosporins are oral agents?

Cefpodoxime proxetil and cefdinir.

What are the 4th and 5th generation cephalosporins?

Cefepime (4th generation) and ceftaroline fosamil (5th generation).

What is the significance of the oxime moiety in cefepime?

It enhances resistance to β-lactamase degradation.

What is the unique structural feature of cefepime at C-3?

It contains a quaternary N-methylpyrrolidine group, improving penetration into gram-negative bacteria.

What is cefepime primarily used for?

Treatment of gram-negative infections with broader activity than 3rd generation cephalosporins.

What is ceftaroline fosamil?

A 5th generation cephalosporin and a water-soluble prodrug.

What are the unique targets of ceftaroline?

It binds PBP-2a for MRSA and PBP-2x for Streptococcus pneumoniae.

What is cefiderocol?

A new cephalosporin approved in 2019, designed for multi-drug resistant organisms.

How does cefiderocol enter bacterial cells?

It uses bacterial iron-transport mechanisms (siderophores) via the catechol group.

What is the mechanism of action of cefiderocol?

It inhibits bacterial PBPs (transpeptidases) to kill bacteria.

What are carbapenems?

Broad-spectrum β-lactam antibiotics with unique structural features for increased stability.

What is imipenem co-administered with and why?

It is co-administered with cilastatin to inhibit renal dehydropeptidase-1, which deactivates imipenem.

How are carbapenems structurally different from penicillins?

Carbapenems lack sulfur in the five-membered ring, and their sulfur is part of the side chain.

What is the functional significance of the olefinic linkage (C-2,3) in carbapenems?

It enhances β-lactam reactivity.

What is the role of the 2-hydroxyethyl group at C-6 in carbapenems?

It increases stability and activity against PBPs.

What do carbapenems inhibit?

They inhibit PBPs and β-lactamases but do not bind or inhibit PBP-2a.

What are the key carbapenem antibiotics?

Meropenem, doripenem, and ertapenem.

What is the unique structural feature of meropenem and doripenem?

Chiral methyl group at C-4, which confers resistance to hydrolysis by dehydropeptidase-1.

What is meropenem primarily used for?

Treatment of severe bacterial infections, including Pseudomonas.

What is doripenem known for?

Similar spectrum to meropenem but more potent against Pseudomonas species.

What is unique about ertapenem's activity?

It is not active against Pseudomonas or Acinetobacter.

What is aztreonam?

A monobactam antibiotic with a monocyclic β-lactam structure.

What is the significance of the sulfamic acid moiety in aztreonam?

It provides unique activity against gram-negative bacteria.

What does aztreonam structurally resemble?

It closely resembles ceftazidime.

What is vancomycin's mechanism of action?

It binds to the D-alanyl-D-alanine terminus of peptidoglycan, inhibiting bacterial cell wall synthesis via reversible inhibition.

How does vancomycin resistance occur?

Replacement of D-alanyl-D-alanine with D-alanyl-D-lactate reduces binding affinity.

What is peptidoglycan?

A polymer of glycan chains (NAG and NAM) cross-linked by peptide chains, forming the bacterial cell wall.

What are the key components of bacterial cell wall cross-linking?

Alternating amino sugars (NAG and NAM) and cross-linked peptide chains.

How many hydrogen bonds does vancomycin form with D-alanyl-D-alanine?

Five hydrogen bonds.

Why is vancomycin less effective against D-alanyl-D-lactate?

It forms only four hydrogen bonds, reducing its inhibitory effect.

What is vancomycin?

A glycosylated hexapeptide antibiotic with activity against Gram-positives, including MRSA.

Why is vancomycin not orally absorbed?

It has high hydrophilicity and is stable in the GI tract but cannot cross the GI membrane.

What are common adverse effects of vancomycin?

Infusion-related events, nephrotoxicity, and ototoxicity.

What are lipoglycopeptides?

Modified glycopeptides (e.g., oritavancin and dalbavancin) with activity against Gram-positives, including MRSA.

How do oritavancin and dalbavancin work?

They inhibit bacterial cell wall synthesis and disrupt cell membrane integrity.

What is daptomycin?

A negatively charged lipopeptide antibiotic active against Gram-positives.

What is the mechanism of action of daptomycin?

It interferes with cell wall synthesis and causes membrane depolarization.

Why does resistance to daptomycin occur?

Gram-positive bacteria may modify their membranes to prevent binding of the daptomycin-calcium complex.

What are polymyxins?

Polypeptide antibiotics (e.g., polymyxin B and E) that disrupt bacterial outer membranes.

What is the mechanism of action of polymyxins?

They bind to LPS in Gram-negative bacteria and disrupt the outer membrane, leading to cell death.

How does resistance to polymyxins develop?

Bacteria modify LPS (e.g., add cationic groups) to prevent polymyxin binding.

What is bacitracin?

A mixture of peptides that interferes with bacterial cell wall biosynthesis.

What is the spectrum of activity of bacitracin?

Active against Gram-positive bacteria.

Why is bacitracin primarily used topically?

It is neurotoxic and nephrotoxic when used systemically.

What are common uses of bacitracin?

Prevention of infections in minor cuts, scrapes, and burns.