Antimicrobial Drugs

antimicrobial drugs - microbiology

nucleoside/nucleotide analogue

inhibit nucleic acid synthesis through incorporation of DNA or RNA

• stop nucleotides from being added or altering base-pair properties

specificity of nucleoside/nucleotide analogues

• some need viral enzyme to activate it

• some have higher affinity for viral polymerases than host polymerase

  • more damage done to rapidly replicating viral genome than host genome

acylclovir

example of nucleoside analogue

antiviral drug targets

• viral enzymes critical to replication

  • fusion

  • release

  • synthesis

  • HIV integrase

antifungal drugs

• increase plasma membrane permeability

• disrupt cell wall synthesis

• interfere with nucleic acid synthesis

major targets of antifungal drug

1. ergosterol synthesis (in place of cholesterol, cell walls)

2. chitin synthesis

3. beta glucan synthesis

antiparasitic drugs

• eukaryotic cell targets (not selective and can be harmful to host)

• little research and development

  • mostly rare in global North

• most interfere with protein synthesis of protozoa or neuromuscular functions of worms

antibiotic mechanisms of action

1. inhibition of cell wall synthesis

2. disruption of cell membrane function

3. inhibition of protein synthesis

4. inhibition of nucleic acid synthesis

5. prevention of folic acid synthesis

beta lactam antibiotics

• most diverse, commonly used class of antibiotics

• inhibit cell wall synthesis, effective only for growing cells

• NO impact on existing peptidoglycan

1. bind and irreversiblyninhibit PBP

2. stop transpeptidase (a PBP) activity

3. stops linking of subunits in cell wall (only new parts of wall)

4. cell lyses once wall is compromised

vancomycin

• non beta-lactam cell wall inhibitor

• LARGE glycopeptide that binds to the peptide side chain that physically blocks transglycosylation and transpeptidation

• “last resort” for gram positive b-lactam resistant drugs

• administered via IV

gram negative bacteria

what is vancomycin inactive against?

too large for outer membrane penetration and porin channels of gram negative

why is vancomycin only used against gram positive bacteria

polymixn B

interacts with phospholipids and lipopolysaccharides in outer membranes and compromises its integrity in gram negative bacteria

• topical applications, not given orally

fluoroquinolones

inhibit prokaryotic topoisomerases (ex. DNA Gyrase) to inhibit replication

chloramphenicol

• bind to 50S ribosomal subunit

• prevent peptide bond formation

• stop protein synthesis

aminoglycosides

• bind to 30S ribosomal subunit

• impair proofreading which makes faulty proteins

tetracyclines

• bind the 30S ribosomal subnit

• block the binding of tRNAs which inhibits protein synthesis

reason for toxicity of protein synthesis inhibitors in humans

prokaryotes and human mitochondria both have 70S (50S + 30S) ribosomes

sulfonamides

analogues of essential metabolites used in folic acid synthesis

• competitive inhibitor of enzyme #1 vs PABA

• more PABA = drug less likely to work

potential side effects of antibiotic use

• direct tissue damage from drug toxicity

• allergic reactions

• disruption of normal microbiota and opportunistic infection

minimum inhibitory concentration (MIC) test

lowest concentration of a specific antimicrobial drug needed to prevent the growth of a given bacterial strain in vitro

innate drug resistance

• naturally lacking drug targets (ex. mycoplasma lacks cell wall, b-lactam ineffective)

• outer membrane of gram negative bacteria blocks many medications

acquired drug resistance

• spontaneous mutations

• horizontal gene transfer

acquisition of drug resistance

mainly conjugation, sometimes transformation

it takes energy to maintain and replicate the plasmid, it must be useful or be degraded

why do plasmids with no fitness benefits not last in bacterium

evolution of antibiotic resistance

1. variation

2. selective pressure

3. heredity

4. time

mechanisms of antibiotic resistance

1. efflux

2. enzyme bypass/overproduction

3. inactivation of antibiotic

4. target modification

5. blocked penetration

blocked penetration

alteration of porins to prevent entry of drugs

drug inactivation

antibiotic inactivating enzymes like beta lactamases

target modification

minor structural changes that prevent binding

ex. PBPs for b-lactam and ribosomal subunits for macrolides

enzymatic bypass

use of an alternate metabolic pathway or overproduction of target enzyme so antibiotic cannot compete

efflux pump

active transport pushes antibiotics out of cell

bacteriostatic

reversibly inhibit growth of bacteria to allow good microbes to destroy pathogens

bacteriocidal

kill bacteria