Antibiotics Lecture 16 Flashcards
Paul Elrich 1909 first synthetic anti microbial drug
Arsenic compound Salvarsan
Treatment of syphilis
Alexander Fleming 1928 first natural anti microbial
Penicillian
Gerhard Domagk 1930 synthetic dye
Prontosil
Treatment of severe streptococcus infection
Foundation of sulfa drugs
Breakdown product of prontosil and sulfanilamide
Dorothy Hodgkin 1946
X-ray crystallography to help determine penicillin structure
Lead to the first semisynthetic anti microbial
Seaman Waksman 1940
Discovery of actinomycin, streptomycin neomycin from streptomyces spp.
Source of more than half of natural anti microbials
Bacteriostatic drugs
Bacteriostats can be effective in patients with a healthy immune system
Bactericidel drugs
Drugs needed for immunocompromised patients
First choice for life threatening infections (pneumonia and endocarditis)
Narrow spectrum anti microbial
Target specific subsets of bacteria such as gram positive or gram negatives
Used after identification of bacteria is made
Broad spectrum anti microbial
Target wide variety of bacteria
Used waiting for identification results
Drug dosage
Determined in order to Dina a good balance between effective ness and minimal side effects
Includes amount of drug and interval of administration
Body mass needed and the bodies ability to metabolize and eliminate drug and bacteria
Route of transmission
Oral administration is generally preferred, as
patients can easily self-dose at home
– Not all drugs are absorbed easily through the GI tract (ie niclosamide for tapeworms)
– When oral administration is not possible, the drug
must be administered via a parenteral route
• Intravenous, intramuscular, or subcuticular injection
Intravenous injection
is often preferred in health
care settings, because higher blood plasma levels of drug are possible vs. oral route or even intramuscular injection
Drug interactions synergistically
and become
more effective together
Drug interactions antagonistically
can become
ineffective or harmful
Selectively toxic for antibacterial drugs
harmful to pathogen but not to host
Antibacterial drugs mode of action
mechanism by which they are toxic to bacteria
• General mechanisms:
1. Inhibition of cell wall synthesis
2. Interference with DNA or RNA activity
3. Disruption of the plasma membrane
4. Interference with protein synthesis
5. Disruption of metabolic pathways
Inhibition if cell was synthesis
The β-lactams
– Penicillins, cephalosporins, monobactams, carbapenems
- All have a structure called lactam ring in core
- also known as a penicillin-binding
protein (PBP)
—————
- blocks the crosslinking of peptide chains during the biosynthesis of new peptidoglycan in the bacterial cell wall
β-lactamase enzymes secreted by resistant organisms break
this ring
Inhibition of Cell Wall Synthesis.
Glycopeptides, polypeptides
– Vancomycin, bacitracin
Vancomycin binds to the exposed ends of cell wall precursors, preventing them from being incorporated into peptidoglycan
——active against gram positive only
Bacitracin blocks the movement of peptidoglycan precursors
from the interior to the exterior of the cell
– Nephrotoxic, so usually only used topically in ointments
Inhibition of Nucleic Acid Synthesis
Nitroimidazoles
Metronidazole intereferes with DNA replication, also works as an antiprotozoan
Inhibition of Nucleic Acid Synthesis
Rifamycins
Rifampin blocks bacterial RNA polymerase activity
Inhibition of Nucleic Acid Synthesis
Quinolones, fluoroquinolones
Nalidixic acid, ciprofloxacin, levofloxacin inhibit
bacterial DNA gyrase activity
• Phototoxic, neurotoxic, cardiotoxic, glucose regulation
problems, tendon rupture
Inhibition of Membrane Function
Polymyxins
only polymyxin B and polymyxin E (Colistin) have been used clinically
-Very nephrotoxic and poorly absorbed orally, so usually used topically or as a bowel decontaminant
Daptomycin
– structurally different than polymyxin, but disrupts
membranes as well
– Safer for IV use
Inhibition of Protein Synthesis 30s
Drugs that bind to the 30s ribosomal subunit
- Causes mismatches between codons an anticodons, causing faulty protein manufacture including membrane-disrupting proteins
Inhibition of Protein Synthesis
30s ribosomal
Aminoglycosides
streptomycin, gentamycin, neomycin,
kanamycin
• Nephrotoxic, neurotoxic, ototoxic
Inhibition of Protein Synthesis
30s ribosomal
Tetracyclines
tetracycline, doxycycline, tigecycline
• Phototoxic, hepatotoxic, tooth discoloration
Inhibition of Protein Synthesis 50s
Drugs that bind to the 50s ribosomal subunit
– Prevents protein synthesis by inhibiting peptide
bond formation between particular amino acids
Inhibition of Protein Synthesis 50s
Macrolides
erythromycin, azithromycin, telithromycin
• Hepatotoxic, particularly telithromycin
Inhibition of Protein Synthesis 50s
Lincosamides
lincomycin, clindamycin
Inhibition of Protein Synthesis 50s
Chloramphenicol
first broad-spectrum antibiotic
• Serious side effects including lethal grey baby syndrome,
suppression of bone marrow production, aplastic anemia
Inhibition of Protein Synthesis 50s
Oxazolidinones
linezolid
• works differently by preventing formation of initiation complex and
interfering with A site to P site transition of tRNA/peptide complex
Antimetabolites (competitive inhibitors)
Sulfonamides
• Are structural analogs of para-aminobenzoic acid (PABA)
that is an early intermediate in folic acid synthesis
• Inhibits dihydrofolic acid synthesis → folic acid synthesis
→purine & pyrimidine synthesis
Antimetabolites (competitive inhibitors)
Trimethoprim
• is a structural analog of dihydrofolic acid
Antimetabolites (competitive inhibitors)
Isoniazid
• causes the formation of altered NAD (isoniazid-nicotinamide adenine dinucleotide) and NADP (isoniazid-
nicotinamide adenine dinucleotide phosphate) which ultimately impacts mycolic acid synthesis
