Beta-Lactam Pharmacology & MedChem Part 1

What are examples of microorganisms?

Bacteria, viruses, fungi, and parasites

What does the term antibiotic encompass?

Antibacterial, antiviral, antifungal, and antiparasitic agents

Define antimicrobial molecules

Ligands whose receptors are microbial proteins

How are antibiotics classified?

Class and spectrum of microorganism it kills

Biochemical pathway it interferes with

Chemical structure of drug

What is a crucial consideration when choosing antibiotics?

Can the drug penetrate to the site of infection?

Poor penetration into anatomical compartment = higher likelihood of failure

What does penetration of drug into an anatomical compartment depend on?

1. Physical barriers that the molecule must traverse

2. Chemical properties of drug

3. Presence of multi drug transporters

What is a special consideration regarding antibiotic penetration of the CNS?

Guarded by the blood-brain barrier (BBB)

Infection decreases its integrity = some antibiotics can gain access

What is a consideration regarding antibiotic penetration of the eye?

Poor drug penetration from plasma

Typically directly administer antibiotics through eye drops

What is a consideration regarding antibiotic penetration of abscesses?

Poor drug penetration = likely need to be drained before treatment

Describe the relationship between inflammation and blood flow

Inflammation can restrict blood flow

Describe the structure of Gram positive bacteria

Inner membrane covered by a thick peptidoglycan layer (cell wall)

No outer membrane or periplasmic space (very small)

Describe the structure of Gram negative bacteria

Inner membrane covered by a thin peptidoglycan layer (cell wall) that is within the large periplasmic space between the inner membrane and outer membrane

What is a major challenge with Gram negative bacteria?

The outer membrane is like a plastic wrap, making it difficult for anything to get through it

UNLESS something chemically permeates it

What makes up the cell membrane versus the cell wall?

Cell membrane = phospholipids

Cell wall = peptidoglycans

What is the target of all beta-lactam antibiotics?

Penicillin binding protein (PBP)

What is the general MOA of beta-lactams?

Target and inhibit cell wall synthesis (peptidoglycan)

What are the four main classes of beta-lactams?

Penicillins

Cephalosporins

Carbapenems

Monobactams

What are the four classes of antibiotics within penicillins?

Natural penicillins

Aminopenicillins

Beta-lactamase resistant penicillins

Beta-lactam/beta-lactamase inhibitors

Where can various side chains attach to beta-lactams?

At the H2N on the far left side of the molecule

What is a major benefit of D-configured amino acids in peptidoglycan?

D-configuration allows amino acids to resist getting cleaved

Means that peptidoglycan layers are resistant to degradation

Host proteases cannot process D-amino acids

What is the specific MOA of beta-lactams?

Inhibit synthesis of the bacterial peptidoglycan wall by inhibiting the last step in peptidoglycan synthesis

Prevents PBP from interacting with portions of proteins to form crosslinks that form peptidoglycan

What is the function of penicillin binding protein (PBP)?

Catalyzes the formation of the key cross link between the D-peptide and the NAM/NAG glycan

What is required for PBP catalysis?

A key serine residue (covalent intermediate)

How is the serine residue modified by beta-lactams?

Covalently modified

What do beta-lactams mimic?

D-Ala-D-Ala stub

How is PBP inactivated?

beta-lactam four membered ring breaks apart

CH2O (previously ketone) binds to PBP to become permanently inactivated

What are common features of beta-lactams?

High ring strain

Tight bond angles

Decreased resonance stabilization

REACTIVE TOWARDS NUCLEOPHILES

Define a lactam

A cyclic amide

What does a beta-lactam mean?

The amine is attached in a beta configuration to the carbonyl

Describe the structure of penicillins

beta-lactam ring attached to a 5 membered ring with a sulfur

Describe the structure of cephalosporins

beta-lactam ring attached to a 6 member ring with a sulfur

Describe the structure of carbapenems

beta-lactam ring attached to a 5 membered ring with a double bond and no sulfur

Describe the structure of monobactams

beta-lactam ring, not attached to anything else

Define the eagle effect of antibiotics

Increased concentrations of an antibiotic above a certain level can actually reduce its effectiveness

What types of infections are beta-lactams not effective on?

Infections with large numbers of bacteria

Why are beta-lactams not effective against infections with large numbers of bacteria?

Crowded bacteria = limited nutrients = no growth

Bacteria not growing = no need to synthesize a cell wall

PBP expression is only increased during bacterial replication

How does bacterial resistance develop?

Infection is treated with antibiotics and most bacteria are eliminated

The few that survive have a mutation that allows them to survive and make them resistant

Resistant bacteria grow, even in presence of antibiotic

What are the four major mechanisms of bacterial resistance?

1. Production of microbial enzymes that metabolize the antibiotic

2. Enhanced export of antibiotic by efflux pumps

3. Porin mutations

4. Change in target protein

Define beta-lactamases

Enzymes that destroy beta-lactams

How do beta-lactamases destroy beta-lactams?

Hydrolyze beta-lactam ring before it can react with PBP

How are beta-lactamases overcome?

With beta-lactamase inhibitors

What are examples of beta-lactamase inhibitors?

Clavulanic acid

Tazobactam

Sulbactam

What type of bacteria are antibiotic efflux pumps exclusive to?

Gram negative bacteria

What do porin mutations result in?

Reduced permeation of drug into bacteria

What type of bacteria are porins are exclusive to?

Gram negative bacteria

Where are porins located?

In the outer membrane of Gram negative bacteria to allow access of drugs into the periplasmic space

How does a mutation in the PBP binding site change the target protein of beta-lactams?

beta-lactams can no longer bind to PBP

PBP still capable of catalyzing reaction to make peptidoglycan cell wall

What is the most common adverse effect of beta-lactams?

Allergies (Type I and type IV)

Describe type I hypersensitivity reactions

Immediate, ex: anaphylaxis

Serious but rare

No reaction on first exposure, fast reaction second exposure

Antibody-mediated

Describe type IV hypersensitivity reactions

Delayed, e.g. rash

Reaction on first exposure, takes a few days to develop

T-cell mediated

What is a significant DDI of beta-lactams?

Potential warfarin interactions

All antibiotics have the potential to slow coagulation and increase bleeding

How do antibiotics interact with warfarin?

Disrupt normal flora in the gut that produces vitamin K required for clotting

Concerning if a patient is already taking an anticoagulant

What are other significant adverse effects of beta-lactams?

GI effects = nausea, vomiting, and diarrhea

How do beta-lactams cause GI adverse effects?

Changes composition of GI tract microflora to eliminate sensitive bacteria

What are rare adverse effects of beta-lactams?

Bone marrow depression, granulocytopenia, and hepatitis

What are IV related adverse effects of antibiotics?

Injection site reactions

What are beta-lactams not stable in the presence of?

In the presence of bases, acids, and nucleophiles

How are beta-lactams chemically fragile?

Slow hydrolysis in water

Accelerated by heat, acid, or base

Reacts with alcohols and amines

What are the three reasons that make beta-lactam stability a concern?

1. Allergies

2. Storage conditions

3. Drug combinations

Define a hapten

A small molecule that when alone is harmless, but when attached to a protein causes an immune response

beta-lactams are haptens

What is used in a penicillin skin test for verifying penicillin allergies?

Penicilloyl-polylysine