Antibiotics Flashcards
What are antibiotics?
Greek: anti (against) bios (life)
- ‘Chemical compounds used to treat infections caused primarily by bacteria; they should be sufficiently non-toxic to be given to the infected host’
- Used to supplement the body’s natural defenses to a bacterial infection by either killing bacteria (bacteriocidal antibiotics) inhibiting them (bacteriostatic antibiotics)
- ‘Selective poisons’ for treating bacterial infections not viral
How are antibiotics traditionally classified?
Traditionally ‘classified’ on their chemical / biosynthetic origin
- Natural antibiotics: (‘true antibiotics’); produced naturally by fungi or bacteria to selectively inhibit the growth of others (Penicillium chrysogenum produces penicillin)
- Semi-synthetic antibiotics: chemically modified natural antibiotics (e.g. ampicillin)
- Totally synthetic antibiotics: manufactured (e.g. trimethoprim)
Antibiotics are ‘clustered’ within a large group of drugs called what?
‘Antimicrobials’ or ‘Chemotherapeutic Agents’
What are the 4 major mechanisms of antibiotic action?
- Cell wall synthesis inhibitors
- Nucleic acid inhibitors
- Protein synthesis inhibitors
- Metabolism inhibitors
The β-Lactam Antibiotics: State the functional group of the penicillins
How do they differ?
Core functional group is the peniciilin nucleus made up with the beta lactam ring combined with the thiazolidine ring
It is an analogue of the D-Ala-D-Ala (the final 2 residues of the pentapeptide crossbridge) and is the (inhibitory) substrate for transpeptidase enzymes
How do the penicillins differ?
- Penicillin G was naturally idenfied from penicillium chrysogenum. Growing it this bacterium on phenoxyacetic acid allowed us to change the structure of penicillin G (intravenous administration) to the more acid stable penicillin V (can be taken orally becuase it is not hydrolysed by stomach acid)
- Amoxicllin was chemically modified to have a longer half life, lower toxicity at a higher concentration and acif stable
- Methicillin is the highly modified version
Describe penicillin discovery and refinement?
Flemming→ Discovered penicillin G production from penicillin chrysogenum
Florey and Chain→Scaled up to produce large quantities of the product
Hodgkin→ Solving of the structure of Peniciilin by X-ray crystallography
Describe the inhibition of Transpeptidase by β-Lactam Antibiotics
- β-lactam antibiotics inhibit the transpeptidase (similar structure to D-alanyl D-alanine in the peptide chain)
- competitive inhibition; irreversible binding
State the clinical usages of β-Lactam antibiotics
- Upper respiratory tract infections-URTI (eg. tonsillitis)
- Lower respiratory tract infections-LRTI (eg. pneumonia)
- STI (eg. gonorrhoea, syphilis)
- Skin and tissue infections
Broad spetrum antibiotic
NB. Hypersensitivity and anaphylactic shock in some patients; alternative antibiotics warranted
Describe antibiotic usage worldwide
- An estimated 10,000 metric tons of antimicrobial agents are manufactured worldwide per year
- The β-lactam antibiotics make up 50% of antibiotics used and include cephahalosporins (30%), penicillins (7%), and other β-lactams (15%)
- “Other” includes tetracyclines, aminoglycosides, and all other antimicrobial drugs
Provide a brief history of antibiotics
Describe the quinolones
- Discovered by George Lesher, 1962
- Used for UTI
- 10,000 analogues of the orignal compounds have been synthesised
- 6 FDA approved (for medical use in humans)
- 24% world’s manufactured antibiotics
- Synthetic antibacterial compounds
- DNA gyrase inhibitors
- Found in all bacteria therefore broad spectrum (activity against Gram+/- bacteria)
- Derivatives of nalidixic acid (fluorinated)
- Quinoline backbone (2 membered ring)
- Functional R-group
- floroquniolones have a flourine group
Describe the mechanism of action of quinolones
- Quinolone antibiotics interfere with changes in DNA supercoiling by binding to DNA gyrase (bind to topoisomerase II [1st and 2nd generation Qs] or topoisomerase IV [3rd and 4th generation Qs])
- Prevent DNA unzipping
- This leads to the formation of double-stranded DNA breaks and cell death
What are the clinical usages of quinolones
- UTIs
- Multi drug resistant (MDR) Infections
- Pyelonephritis (kidney infection)
- Prostatitis (prostate infection)
- Pneumonia
- (disseminated LRT infections)
Highly restricted use in children in UK (anthrax or cystic fibrosis pulmonary infection) – musculoskeletal side effects
Describe the Macrolides
Discovered in 1952 – erythromycin from Streptomyces erythraeus
Natural products – polyketides
20% world’s manufactured antibiotics
- Macrocyclic lactone ring
- Mostly Gram + (limited Gram- activity) considered broad spectrum
- Most active against Gram+ cocci (mainly staphylococci and streptococci)
- Macrolides are also active against Mycobacteria, Mycoplasma, Ureaplasma, spirochetes, and other organisms.
Decsribe the mechanim of action of macrolides
- Protein synthesis inhibitors
- Reversible binding (high affinity but no covalent bonding which allows release and reuse) to the P site on 50S ribosomal subunit
- Bacteriostatic (arrest trasnslational activity of the bacterial ribosomes)
- Disruption of proteome leading to cell death
Describe aminoglycosides
Natural products - amino sugars bonded by glycosidic bonds
Identified in 1944 – By Waksman and Schatz
- Streptomycin from Streptomyces griseus (first treatment for TB)
- Bactericidal (aerobic Gram-)
- Mostly G- bacteria [not anaerobes] (+ Mycobacteria)
- Streptomycin
- Kanamycin
- Tobramycin
- Gentamycin
- Neomycin
- IV adminstration (otherwise destroyed by stomach acid)
Explain the mechanisms of action of aminoglycosides
- Protein synthesis inhibitors
- Bind to the aminoacyl site of 16S rRNA in 30S subunit of the ribosome (irreversible-covalent suicide inhibitor MOA)
- Cause mis-incorporation of amino acids into elongating peptides
- Incorporation of misfolded membrane proteins into the cell envelope (wall) which forms pores and leads to increased drug uptake
- Increase in ribosome binding
- Cell death
Describe the tetracyclines
- Natural products – (Aureomycin (CTC) from Streptomyces aureofaciens 1945 – Identified by Benjamin Duggar)
- Broad spectrum (better against G+)
- Tetra- (4) -cycl- (hydrocarbon ring) -ine (derivative)
- Derivatives of polycyclic naphthacene carboxamide
- Bacteriostatic
Explain the mechanism of action of tetracyclines
- Protein synthesis inhibitors
- Inhibit binding of aminoacyl-tRNA to mRNA-ribosome complex in the A site of 30S robosomal subunit
- No further elongation of amino acid chain→Stall protein synthesis
- Reversible binding
- Cause disruption to proteome leading to bactiostasis
- Also bind matrix metalloproteinases (useful!)
What are the clinical uses of tetracyclines?
- UTI
- U/LRTI
- GI Tract infections
- Chlamydia (if allergic to β-lac or macrolides)
- Acne
- Rickettsia
- Brucellosis
- Spirochetal infections (syphilis and Lyme disease (borreliosis))
- Anthrax, plague, Legionnaires’ disease
- Cholera
Tetracyclines: Why are they useful chemicals?
antitumorigenic properties as they bind to matrix metalloproteinases
With the addition of different derivatives have antifungal action
Name other tetracyclines
- Chrophenol
- Glycopeptides
- Ansamycins
- Spretogramins
- Sulfonamides
- Oxazolidinones
- Lipopeptides
State antibiotics for animal and human use
- Penicillins
- Cephalosporins
- Qinolones
- Fluorqinolones
- Tetracyclines
- Macrolides
- Sulfas
- Glycopeptides
- Others
