CELL WALL INHIBITORS

The bacterial cell wall, specifically the peptidoglycan layer

What structure do cell wall inhibitors target in bacteria?

Mammalian cells do not have cell walls, so these drugs do not affect host cells.

Why are cell wall inhibitors selectively toxic to bacteria?

Glycan units connected by peptide cross-links.

What is peptidoglycan composed of?

Against actively proliferating (growing and dividing) bacteria

When are cell wall inhibitors most effective

They have little to no effect on bacteria that are not actively dividing.

Do cell wall inhibitors affect non-growing bacteria?

The β-lactam ring, which is critical for their antimicrobial activity.

What is the essential structural feature of β-lactam antibiotics?

β-lactam antibiotics, vancomycin, and daptomycin

What are the major drug groups that inhibit bacterial cell wall synthesis?

Penicillins

Are among the most widely effective and least toxic drugs known, but increased resistance has limited their use

The R substituent attached to the 6-aminopenicillanic acid residue

What structural feature varies among penicillin family members?

• Antimicrobial spectrum

• Stability to stomach acid

• Cross-hypersensitivity

• Susceptibility to β-lactamases (bacterial degradative enzymes)

Variation in the R substituent of penicillins affects which important characteristics? (List all)

The 6-aminopenicillanic acid residue.

To what core structure is the R side chain of penicillins attached?

β-lactamases (bacterial degradative enzymes).

What enzyme group can degrade penicillins depending on their R substituent?

The nature of the R side chain attached to the 6-aminopenicillanic acid nucleus.

What determines the antimicrobial spectrum and acid stability of penicillins?

The last step of cell wall synthesis — transpeptidation (cross-linkage).

What is the main step in bacterial cell wall synthesis that penicillins inhibit?

The cell wall becomes unstable, exposing the osmotically fragile membrane, leading to cell lysis.

What is the consequence of blocking transpeptidation in bacteria?

Through osmotic pressure or activation of autolysins.

How does cell lysis occur after penicillin exposure?

They are bactericidal and act in a time-dependent manner.

Are penicillins bacteriostatic or bactericidal?

Rapidly growing organisms that synthesize a peptidoglycan cell wall.

Penicillins are only effective against what type of organisms?

Mycobacteria, protozoa, fungi, and viruses.

Which organisms are naturally resistant to penicillins because they lack peptidoglycan?

Bacterial enzymes involved in cell wall synthesis and maintenance of bacterial morphology.

What are penicillin-binding proteins (PBPs)?

They inactivate PBPs, preventing cell wall synthesis and causing morphologic changes or lysis.

What happens when penicillins bind to PBPs?

Alterations in PBPs that reduce penicillin binding.

What provides bacterial resistance related to PBPs?

Methicillin-resistant Staphylococcus aureus (MRSA).

Example of bacteria with altered PBPs causing resistance to penicillins

Formation of cross-linkages between peptidoglycan chains via transpeptidase activity.

What reaction do some PBPs catalyze that is essential for cell wall integrity?

They inhibit the transpeptidase-catalyzed formation of cross-links in the peptidoglycan cell wall.

How do penicillins affect transpeptidase?

Degradative enzymes produced by bacteria that participate in normal cell wall remodeling

What are autolysins?

In the presence of penicillins, autolysins continue degrading the cell wall even though new cell wall synthesis is blocked → leading to cell destruction.

How do autolysins contribute to penicillin's antibacterial action?

• Inhibition of cell wall synthesis

• Destruction of existing cell wall by autolysins

The antibacterial effect of penicillins is due to which combined actions?

Their ability to cross the bacterial peptidoglycan cell wall and reach penicillin-binding proteins (PBPs) in the periplasmic space.

What determines the antibacterial spectrum of different penicillins?

Size, charge, and hydrophobicity of the β-lactam antibiotic

What physicochemical factors of β-lactam antibiotics influence their ability to reach PBPs?

Gram-positive organisms have easily traversed cell walls, allowing penicillins to reach PBPs readily (when resistance is absent).

Why are gram-positive bacteria generally more susceptible to penicillins?

An outer lipopolysaccharide membrane that acts as a barrier to water-soluble penicillins.

What structural feature of gram-negative bacteria limits penicillin entry?

They contain porins, which are water-filled protein channels in the lipopolysaccharide layer that permit antibiotic entry.

How do gram-negative bacteria allow penicillins to enter despite the outer membrane barrier?

Because their size, charge, or hydrophobicity prevents effective passage through porin channels to reach PBPs.

Why do some penicillins have poor activity against gram-negative organisms?

The periplasmic space, where PBPs are located.

Where must penicillins reach to exert their antibacterial effect?

They are obtained from fermentations of the fungus Penicillium chrysogenum.

From what organism are natural penicillins (penicillin G and V) obtained?

By chemically attaching different R groups to the 6-aminopenicillanic acid nucleus.

How are semisynthetic penicillins like amoxicillin and ampicillin created?

Benzylpenicillin

What is penicillin G also called?

• Gram-positive cocci

• Gram-negative cocci

• Gram-positive bacilli

• Spirochetes

Penicillin G is the cornerstone therapy for which types of organisms?

β-lactamases (penicillinases)

What enzyme inactivates penicillins and contributes to bacterial resistance?

• Gas gangrene (Clostridium perfringens)

• Syphilis (Treponema pallidum)

Despite resistance, what infections still use penicillin G as the drug of choice?

penicillin

Remains the drug of choice for the treatment of gas gangrene (clostridium perfringens) and syphilis (treponema pallidum)

Penicillin V has a similar antimicrobial spectrum to penicillin G

How does the spectrum of penicillin V compare to penicillin G?

Because it has poor oral absorption, making blood levels unreliable

Why is penicillin V not used to treat bacteremia?

Penicillin V is more acid stable

Which is more acid-stable: penicillin G or penicillin V?

Its greater acid stability allows better survival in the stomach, making it effective for oral treatment of infections.

Why is penicillin V commonly used orally?

• Streptococcus pneumoniae (resistance increasingly seen)

• Streptococcus pyogenes

• Streptococcus viridans group

Which gram-positive cocci are typically susceptible to penicillin G?

• Bacillus anthracis

• Corynebacterium diphtheriae

Which gram-positive bacilli are covered by penicillin G?

• Neisseria gonorrhoeae

• Neisseria meningitidis

Which gram-negative cocci are susceptible to penicillin G?

Clostridium perfringens

Which anaerobic organism is classically treated with penicillin G?

• Treponema pallidum (syphilis)

• Treponema pertenue (yaws)

Which spirochetes are targeted by penicillin G?

Streptococcus pneumoniae

Is a major cause of bacterial pneumonia in all age groups

Penicillin G

Streptococcus pneumoniae is resistant to this

Mutations in one or more penicillin-binding proteins (PBPs).

What causes increased resistance of S. pneumoniae to penicillin G?

Silver nitrate drops in eyes

Prevent gonococcal ophthalmia in newborns

ceftriaxone

Backup: azithromycin and spectinomycin

How are penicillinase-producing Neisseria gonorrhoeae strains treated?

Treponema pallidum (a spirochete).

What organism causes syphilis?

A single treatment is curative for primary and secondary syphilis, and no antibiotic resistance has been reported

Why is penicillin G the preferred drug for syphilis treatment?

Syphilis

A contagious venereal disease that progressively affects many tissues.

• Methicillin

• Nafcillin

• Oxacillin

• Dicloxacillin

Which drugs belong to the antistaphylococcal penicillins?

They are β-lactamase (penicillinase)–resistant

What major feature makes antistaphylococcal penicillins useful against staphylococci?

Antistaphylococcal penicillins

Primary clinical use is the treatment of infections caused by penicillinase-producing staphylococci, including MSSA (methicillin-sensitive Staphylococcus aureus)

Due to toxicity, specifically interstitial nephritis.

Why is methicillin not used clinically in the United States?

It is used in laboratory testing to identify methicillin-resistant Staphylococcus aureus (MRSA) strains.

If methicillin is not used clinically, what is its current role?

MRSA

causes serious community and nosocomial (hospital-acquired) infections and is resistant to most β-lactam antibiotics

They have minimal to no activity against gram-negative organisms.

Do penicillinase-resistant penicillins have activity against gram-negative bacteria?

MSSA produces penicillinase, and these drugs are resistant to penicillinase degradation

What characteristic of MSSA makes antistaphylococcal penicillins effective against it?

Ampicillin and amoxicillin.

Which drugs are classified as extended-spectrum penicillins?

They have a spectrum similar to penicillin G but are more effective against gram-negative bacilli.

How does the antibacterial spectrum of ampicillin and amoxicillin compare to penicillin G?

Listeria monocytogenes.

Which gram-positive bacillus is treated with ampicillin (± gentamicin) as the drug of choice?

ampicillin (± gentamicin)

Is the drug of choice for the gram-positive bacillus Listeria monocytogenes and susceptible enterococcal species

Susceptible enterococcal species.

Besides Listeria, what other organisms can ampicillin treat effectively?

They are widely used for respiratory infections.

What is a common clinical use of extended-spectrum penicillins in the respiratory system?

Amoxicillin

Is employed prophylactically by dentists in high-risk patients for the prevention of bacterial endocarditis

To prevent bacterial endocarditis in high-risk patients.

Why do dentists use amoxicillin prophylactically in some patients?

Plasmid-mediated penicillinase (β-lactamase) inactivation

What is the major cause of resistance to ampicillin and amoxicillin?

• Escherichia coli

• Haemophilus influenzae

Which common gram-negative organisms are often resistant to ampicillin and amoxicillin?

By combining them with β-lactamase inhibitors:

• Amoxicillin + clavulanic acid

• Ampicillin + sulbactam

How can the spectrum of ampicillin or amoxicillin be extended despite β-lactamase–producing organisms?

It protects the drug from enzymatic hydrolysis and extends antimicrobial coverage.

What effect does adding a β-lactamase inhibitor have on these antibiotics?

No. MSSA is resistant unless a β-lactamase inhibitor is added.

Are MSSA strains susceptible to ampicillin or amoxicillin alone?

For synergistic effect, especially against enterococci

Why is gentamicin sometimes added to ampicillin in severe infections?

• piperacillin

• ticarcillin

Called antipseudomonal penicillins due to their activity against Pseudomonas aeruginosa

piperacillin

The most potent antipseudomonal penicillin

parenteral formulations

These antipseudomonal penicillins are available in this formulation only

Because Klebsiella has constitutive penicillinase

Why are ticarcillin and piperacillin not effective against Klebsiella species?

Ticarcillin + clavulanic acid, Piperacillin + tazobactam

Formulating ticarcillin or piperacillin with this extends their antimicrobial spectrum to include penicillinase-producing organisms

Most Enterobacteriaceae and Bacteroides species

Examples of penicillinase-producing organisms included when antipseudomonal penicillins are combined with β-lactamase inhibitors

Effective against many gram-negative bacilli, including Pseudomonas aeruginosa

Activity of antipseudomonal penicillins (piperacillin, ticarcillin)

Gram (+) cocci

• Enterococci

Gram (-) bacilli

• Listeria monocytogenes

Gram (-) rods

• Escherichia coli

• Haemophilus influenzae

• Proteus mirabilis

• Salmonella typhi

Antimicrobial spectrum of ampicillin

Gram (-) rods

• Enterobacter species

• Escherichia coli

• Proteus mirabilis

• Proteus (indole positive)

• Haemophilus influenzae

• Pseudomonas aeruginosa

Antimicrobial spectrum of ticarcillin and piperacillin

Mycoplasma pneumoniae

Organisms naturally resistant to penicillins due to lack of peptidoglycan or impermeable cell walls

Plasmid-mediated β-lactamases

The main mechanism of acquired penicillin resistance in bacteria

Hydrolyzes the cyclic amide bond of the β-lactam ring → loss of bactericidal activity

Effect of β-lactamase on penicillin

Extracellularly

Where do gram-positive bacteria secrete β-lactamases?

In the periplasmic space

Where do gram-negative bacteria inactivate β-lactam drugs?

• Decreased permeability of the outer membrane

• Efflux pumps reducing intracellular drug

• Altered PBPs with lower β-lactam affinity

Mechanisms by which bacteria can survive β-lactam antibiotics besides β-lactamase production

Klebsiella pneumoniae

Example of decreased permeability and efflux pump reducing β-lactam efficacy

Modified PBPs (altered penicillin-binding proteins) with low affinity for β-lactams

Mechanism explaining MRSA resistance to most β-lactams

Certain gram-negative bacteria (example: second and third generation cephalosporin resistance)

β-lactamases that are induced by β-lactam antibiotics (chromosome-associated) can be found in which organisms?

1. Stability of the drug to gastric acid

2. Severity of the infection

Route of administration of β-lactam antibiotics depends on these two factors