Antibacterial Modes of Actions

What does antimicrobial mean?

Any chemicals which kill or inhibit microbial growth in or on a body surface (Fungal, viral, bacteria…)

What does antibacterial mean?

Any chemical which specifically targets bacteria and kills or inhibits its growth.

What does antibiotic mean?

A drug used to treat bacterial infections

What does selective toxicity mean?

Selectively kills or inhibits the target organism, whilst causing no or minimal harm to the host

• We want antibiotics to be selectively toxic

What does bacteriostatic mean?

Slow down or stall bacterial growth

What does bactericidal mean?

Kills bacteria

Why is it harder to find selective toxicity in antifungals / antivirals?

• Fungi are eukaryotic

• Viruses live in host cells so use our cells to replicate

What are ideal properties & activities of antibacterials?

• Specific: the ability of a drug/chemical agent to interact with a defined target

• Selective: selectively kills or inhibits the target organism, whilst causing  no or minimal harm to the host.       

• Less selectivity means more adverse effects

• Bactericidal

• Minimal emergence of resistance  to the drug

What are the pharmacological activities of antibacterials?

• Non toxic to host

• Long plasma half life

• Good tissue distribution

• Low plasma protein binding

• Oral & parenteral (options to treat people)

• No interference with other drugs

Where are the 4 main antibacterial targets in a bacterial cell?

• Cell wall (major target - many drugs target this)

• Protein synthesis

• Cell membrane (fewer drugs target this)

• Nucleic acid (many drugs target)

Why do we have few drugs which target the bacteria cell membrane?

Cell wall as a target

• Unique to prokaryotes

• Provides selective target

• Mainly bactericidal

Protein synthesis as a target

• Many drugs exploit differences between prokaryotic and eukaryotic ribosomes - selective target

• Many drugs are bacteriostatic

Cell membrane as a target

• High similarity to eukaryote cell  membrane

• Few targets selective for bacteria

• Fewer drugs target the cell membrane

Mainly Bactericidal

Nucleic synthesis as a target

Gram Negative bacteria

• Gram negative bacteria

• Stains pink

• E.coli

• Outer-membrane

• Thin peptidoglycan layer

• LPS (red)

• Hard to get into gram negative bacteria because of the charged LPS

• Porin channels

• Any antibiotic to treat gram negative bacteria has to get through porin channels, making them harder to treat

Gram positive bacteria

Peptidogylcan

Most prescribed type of antibiotic

B-Lactams

All contain B-lactam ring

Differences in structure of ring attached to B-lactam and side chains

What is B-lactam 1st mode of action?

The enzyme Penicillin Binding Protein (PBPs) also known as transpeptidases catalyse the crosslinking of the peptide side chains of the peptidoglycan monomer when it is incorporated into the cell wall

Beta lactam antibiotics bind and inhibit action of the PBP enzyme. They mimic the D-alanine D-alamine, forming an antibiotic enzyme complex

What is B-lactam 2nd mode of action?

• The presence of beta lactams stimulate the bacteria to produce enzymes known as autolysins  

• These enzymes breaks  down cell wall

• Leads to cell lysis due to osmotic pressure and loss of integrity of   the cell wall

What are the other classes of antibiotics?

• Glycopeptides

• Fosfomycin

• Cycloserine

• Bacitracin

Antibiotics which target the cell membrane

• Polymyxins

• Lipopeptides

Polymyxin E (Colistin)

Can only be used to target Gram Negative bacteria

Nucleic acid synthesis inhibitors

Protein synthesis inhibitors

• Protein synthesis is similar between eukaryotes and prokaryotes

• Prokaryotes actually synthesise proteins 10x faster than eukaryotes do

• But bacterial and mammalian ribosomes differ in their structure. Prokaryotic subunits are smaller

• Within subunits, the structure also differs

• We can exploit these differences to give us selective drug targets which inhibit bacterial protein synthesis