Lecture 8 Flashcards
Antimicrobial agents are used:
to treat diseases by destroying pathogenic microorganisms or inhibiting their growth at concentrations low enough to avoid undesirable damage to the host
When was penicillin discovered?
1928
When was sulfonamides discovered?
1935
When was penicillin first used in clinical as an effective therapeutic substance?
1940
When was the Streptomycin antibiotic discovered from Streptomyces bacterial species?
1944
Today, 80% of antibiotics are sourced from the bacterial genus __
Streptomyces, actinomycetes
Ideal antimicrobial drugs exhibit _____, which means the drug is harmful to a pathogen without being harmful to the host
selective toxicity
Antimicrobial drugs act in one of the following ways:
1) Inhibition of cell wall synthesis
2) Inhibition of cell membrane function
3) Inhibition of protein synthesis
4) Inhibition of nucleic acid synthesis
How do antimicrobial drugs act to inhibit cell wall synthesis?
The antibiotics inhibit transpeptidation enzymes ( such as PBPs) involved in the building of peptidoglycan layers of the cell wall (by cross-linking of NAG-NAM polysaccharide chain)
As a result, incomplete cell wall builds and cell will lyse and die
What is an example of antibiotics that inhibit cell wall synthesis?
All Beta-lactam antibiotics (penicillin, ampicillin, cephalosporins, cephamycin, carbapenems, etc.) are selective inhibitors of bacterial cell wall synthesis
After inhibiting the transpeptidation reaction, some of the Beta-lactam drugs are involved in the:
inactivation of inhibitors of autolytic enzymes in the cell wall –> the activation of the lytic enzymes leads to cell wall lysis
Do Gram + and Gram - bacteria have different susceptibilities to Beta-lactam antibiotics?
Yes, due to structural differences in their cell walls
______ drugs show a remarkable lack of toxicity to mammalian cells
Beta-lactam
Other antibiotics target cell wall synthesis, such as:
vancomycin, bacitracin, and novobiocin, and other glycopeptide analogues such as teicoplanin and cycloserine
Why do some pathogens show resistance to Beta-lactam antibiotics?
Their ability to produce Beta-lactamases ( or penicillinases) enzymes that inhibit or destroy Beta-lactam compounds
What are some examples of Beta-lactamases that are plasmid-mediated?
Penicillinase, Staphyloccus aureus, Neisseria gonorrhoeae, Haemophilus influenzae, and Enterococci
What are some examples of Bet-lactamases that are chromosomally mediated?
Bacteroides, Acinetobacter, Enterobacter, and Pseudomonas species
A group of B-lactamases termed: ________ confer additional resistance to more B-lactam drugs such as cefotaxime, ceftazidime, or aztreonam
extended-spectrum B-lactamases (ESBLs)
ESBLs are produced by certain species of Gram-negative bacilli, such as:
Klebsiella pneumoniae, and Escherichia coli
Clavulanic acid, sulbactam, and tazobactam are ________
B-lactamase inhibitors
How do Beta-lactamase inhibitors work?
They have a high affinity for Beta-lactamases enzymes, they can bind to them and inhibit them rendering them Beta-lactam resistant pathogen sensitive to Beta-lactam drugs
Inhibition/alteration of cell membrane function:
Polymixins:
disrupt membrane structure and permeability properteries
Inhibition/alteration of cell membrane function:
Nalidixic acid and novobiocin:
Interfere with biosynthetic functions of the cell membrane and inhibit teichoic acid synthesis
Inhibition/alteration of cell membrane function:
Ionophores (Valinomycin):
permit rapid diffusion of specific cations (such as potassium ions) through the membrane
Inhibition/alteration of cell membrane function:
Daptomycin:
-A lipopeptide antibiotic
-It is rapidly bactericidal, it binds to the cell and can cause depolarization of the bacterial membrane. This leads to intracellular potassium release that causes cell death
Inhibition of protein synthesis:
Aminoglycosides (Streptomycin and Gentamycin):
bind with the 30S subunit of the bacterial ribosome causing misreading of mRNA and inhibiting protein synthesis
Inhibition of protein synthesis:
Macrolides, Azalides, Ketolides and Lincosamide drugs:
-Erythromycins, azithromycin, clarithromycin, roxithromycin and ketolide telithromycin and the lincosamide clindamycin
bind to the 50S subunit and inhibit the peptide chain elongation
Inhibition of protein synthesis:
Tetracyclines:
bind reversibly to the 30S subunit of microbial ribosomes and interfere with aminoacyl-tRNA binding
Inhibition of protein synthesis:
Chloramphenicol:
-Binds to the 50S subunit
-It interferes with the binding of new amino acids to the nascent peptide chain, through inhibiting peptidyl transferase
-Chloramphenicol is mainly bacteriostatic
Inhibition of protein synthesis:
Oxazolidinones:
-Process a unique mechanism of inhibition of protein synthesis in Gram-positive bacteria
-They interfere with translation by inhibiting the formation of N-formyl methionyl tRNA, the initiation complex at the 23S ribosome
What is the first antibiotic of the Oxazolidinone group to be commercially available and what is it used to treat?
-Linezolid
-It is used to treat infections caused by vancomycin-resistant Enterococci and even Mycobacterial infections
Inhibition of nucleic acid synthesis:
Rifampin:
Binds strongly to the DNA-dependent RNA polymerase of bacteria. It blocks bacterial RNA synthesis
Inhibition of nucleic acid synthesis:
Quinolones and fluoroquinolones:
Inhibit bacteria DNA gyrases (topoisomerase) thus interfere with DNA replication, transcription, and DNA repair mechanisms
Inhibition of nucleic acid synthesis:
Sulfonamides, trimethoprim, and pyrimethamine:
Inhibit of synthesis of nucleic acids
Aminoglycosides-resistant pathogens produce:
adenylating, phosphorylating, or acetylating enzymes that destroy the drug
How do microorganisms change their permeability to the drug?
Through down-regulation of porin channels required for Beta-lactam entry. (Ex: Enterobacter spp., Klebsiella pneumoniae, and Escherichia coli)
They exhibit resistance to carbapenem antibiotics based on the loss of these porin channel proteins
Resistance to polymyxins is also associated with a change in permeability to the drugs
Streptococci have a natural permeability barrier to ________
aminoglycoside antibiotics
Microorganisms develop an altered structural target for the drug in two ways (explain):
A) Modification in PBPs (mutation or expression of alternative PBPs):
This can lower the ability of Beta-lactam antibiotics to bind to PBPs in the bacterial cell wall. Ex: PBPs of Methicillin-resistant Staphylococcus aureus (MRSA).
Streptococcus pneumonia, and Neisseria spp –> have acquired highly resistant and low affinity PBPs
B) Erythromycin-resistant organisms: have altered receptors on the 50S subunit of the ribosome
Microorganisms develop an altered enzymes that can still preform its metabolic function but is much _____ affected by the drug
less
In Trimethoprim resistant bacteria, the _____ (involved in nucleic acid synthesis) is inhibited far less effectively than in trimethoprim susceptible bacteria
dihydrofolic acid reductase
In some multidrug-resistant Gram-negative pathogens (Ex: Pseudomonas aeruginosa and Acinetobacter spp.) the ___________ in concert with low membrane permeability confers resistance to penicillin and cephalosporins as well as other antibiotics
upregulation of efflux pumps
