MCB 100 Lecture 34: Controlling Microbes in the body- Antimicrobials

Drugs

Chemicals that affect physiology in any manner

Chemotherapeutic agents

drugs that act against diseases

Antimicrobial agents

Drugs that treat infection

Paul Ehrlich

"Magic bullets"
-Arsenic compounds that killed microbes
-Began the concept of chemotherapeutics

Alexander Fleming

Penicillin released from Penicillium

Selman Waksman

Antibiotics
-Antimicrobial agents produced naturally by organisms

Workflow for developing antimicrobials

find antimicrobial agent --> isolate active compound --> chemical synthesis of active compound

Antibiotic "revolution" has helped increase life-spans

After discovery of antibiotics life expectancy rose in many countries
-communicable to non-communicable diseases (cardiovascular disease, cancer, stroke)

Principles of antimicrobials

-successful chemotherapy requires selective toxicity: antimicrobial agent must be more toxic to a pathogen than the host
-antimicrobial drugs constitute largest number and diversity of antimicrobial agents
-fewer drugs to treat eukaryotic infections: often toxic to host because cellular machinery is similar
-antiviral drugs limited: often toxic to host because viruses largely require host factors to replicate

Which of the following best defines selective toxicity for an antimicrobial drug?

When a drug is more toxic to a pathogen than its host

selective toxicity

antimicrobial agent must be more toxic to a pathogen than the host

Targets and Mechanisms of action of antimicrobials
(from most types and frequently used to fewest types and usage)

Most types and frequently used:
-Inhibition of cell wall synthesis
-Inhibition of protein synthesis
-Disruption of cytoplasmic membrane
-Inhibition of general metabolic pathway
-Inhibition of DNA replication
-Inhibition of RNA synthesis
-Inhibition of pathogen's attachment or entry into host cell
Fewest types and usage

Inhibition of cell wall synthesis

-Most common agents prevent cross-linkage of NAM subunits
-Beta-lactams are most prominent in this group
-Functional groups are beta-lactam rings
-Beta-lactams bind to enzymes that cross-link NAM subunits
Mechanism of action: Bacteria have weakened cell walls and eventually lyse

Process: bacterial cell wall made of peptidoglycan, made of NAG-NAM chains that are cross-linked by peptide bridges between NAM subunits
---growth---> new NAG and NAM subunits are inserted into the wall by enzymes, allowing the cell to grow.
---> Beta-lactam interferes with the linking enzymes, so NAM subunits remain unattached to their neighbors. However the cell continues to grow and adds more NAG and NAM subunits. ---growth---> cell bursts from osmotic pressure because peptidoglycan is not maintained.

Common Inhibitors of bacterial cell wall synthesis

-Penicillin G
-Carbapenems
-Cephalosporins
-Penicillins

Chemical Inhibitors of the same process often have similar chemical shapes and properties

Inhibition of protein synthesis

Prokaryotic ribosomes are 70S (30S and 50S)
Eukaryotic ribosomes are 80S (40S and 60S)
Drugs can selectively target translation
Mitochondria of animals and humans contain 70S ribosomes
Can be harmful

Mechanism of action:
some aminoglycosides like streptomycin cause change in 30S shape, so mRNA is misread.
---> tetracycline and some aminoglycosides block docking site of tRNA
---> Chloramphenicol blocks peptide bond formation (amino acids)
--->lincosamids or macrolides bind to 50S subunit, blocking proper mRNA movement through ribosome. Synthesis stops.
---> antisense nucleic acid blocks formation of ribosomal subunits
---> oxazolidinone, inhibition of translation initiation

Which of the following is an actual mechanism of action for an antibiotic that inhibits protein synthesis?

Blocking peptide bond formation & inhibiting translation initiation

Prokaryotes contain _____ ribosomes.

70S ribosome of prokaryotes is composed of smaller 50S and 30S subunits.

The tRNA molecule holding a growing polypeptide chain is at the _____.

P sites

Which category of antimicrobial drug works by changing the shape of a ribosome?

Aminoglycoside- changes the shape of a 30S subunit causing the ribosome to misread the mRNA.

Which category of antimicrobial drug essentially acts to stall a ribosome as it reads mRNA?

Macrolides block the movement of a ribosome along mRNA, so the E site is never emptied and polypeptide formation is stopped.

Chloramphenicol blocks the action of the large (50S) subunit. This essentially _____.

prevents the formation of peptide bonds

Which antimicrobial drugs affect the structure of the ribosome itself?

aminoglycosides, antisense nucleic acids, and oxazolidinones

-Each of these drugs actually modifies or prevents the formation of the complete 70S ribosome.

Which category of drug is complementary to mRNA of the pathogen?

antisense nucleic acids

Disruption of Cytoplasmic Membranes

Amphotericin B specifically targets fungal infections and leishmaniasis
Selectivity is based on specific differences in chemical makeup of cytoplasmic membranes

Inhibition of Metabolic Pathways

antimetabolic agents can be effective when pathogen and host metabolic processes differ

PABA ---> sulfonamides, structural analogs of PABA

Normal function where PABA enters active site for folic acid synthesis in bacteria and protozoa.

INHIBITED FUNCTION: PABA cannot enter due to sulfonamide so folic acid synthesis is inhibited (folic acid not produced)

Inhibition of DNA Replication and RNA synthesis

Nucleotide or nucleoside analogs (nucleoside: adenosine, guanosine, thymidine, cytidine):

-interfere with function of nucleic acids
-distort shapes of nucleic acid molecules and prevent further replication, transcription, or translation.
-**often used against viruses (virus polymerases)
-**effective against rapidly dividing cancer cells

what makes a good antimicrobial?

-readily available
-inexpensive
-chemically stable (long shelf life at room temp)
-easily administered
-nontoxic and nonallergenic
-selectively toxic against wide range of pathogens (but not normal microbiota)

Spectrum of action

the number of different pathogens a drug acts against

narrow spectrum

effective against few organisms

broad spectrum

effective against a large range of organisms:
-may allow for secondary infection or superinfections to develop
-killing of normal microbiota reduces microbial antagonism

Therapeutic Index

is the ratio of the dose of a drug that can be tolerated to the drug's effective dose (50% of patients showing an effect = EC50)

-if therapeutic effect line is higher at the end and if it starts lower near the beginning then its good
-therapeutic index has greater distance from toxic effect then its good