Bacterial Protein Synthesis Flashcards
Outline of Protein Synthesis:
DNA is always replicating.
DNA unzipping to RNA is Transcription
Forming proteins from RNA is Translation
Bacterial Ribosomes:
Made of 2 subunits- 30s + 50s
The 30s is composed of 16s rRNA and 21 polypeptide chains.
The 50s subunits are composed of 5s rRNA, 23s rRNA and 34 polypeptide chains.
3 Phases of Bacterial protein synthesis
Initiation- assembly of components of translation system, the ribosome subunits, mature mRNA, tRNA, GTP as energy source and elongation and initiation factors.
Elongation- addition of amino acids at carboxyl end of growing chain. protein exits through exit tunnel of large subunit.
Termination- When one of the 3 termination codon moves into A site of ribosome which is recognise by a release factor, hyrsolysis of ester bond and new protein is released.
Aminoglycosides:
Examples structure Mode of Action pharmacokinetics spectrum of activity and uses Adverse effects.
Streptomycin, kanamycin, amikacin
Linked ring system composed of aminosugars and aminocyclitol.
Self promoted passage across outer membrane of G-
Active transport across cell membrane, 02 + energy dependant.
Targets the 30s ribosomal subunit and binds irreversibly. streptomycin binds to a specific protein.
Neomycin and kanamycin bind at different sites on 30s and also bind to 50s.
The elongation of the nascent peptide chain is disrupted by the translational inaccuracies such as missreading or premature termination which leads to defective proteins which have altered permeability.
The aminoglycosides have potent bactericidal activity.
Adheres to concentration-dependent killing with a prolonged post-antibiotic effect.
Given by injection or topically as oral and GI absorption is poor. distributes mainly in extracellular space.
2hr serum half-life. rapidly excreted unchanged in the kidney.
Broad spectrum- aerobic G- bacilli e.g. enterobacter, and P. aeruginosa. Also G+s including many staphs and certain mycobacteria
streptococci and enterococci relatively resistant but can be used synergistically with other agents
Gentamicin used for blind therapy or life threatening conditiions.
Low therapeutic index
nephrotoxicity, ototoxicity, neuromuscular blockage.
The Macrolides:
Erythromycin
Clarithromycin
Mode of action
Eryhtromycin:
14-membered macrocyclic lactone ring with 2 attached sugar moieties. used for treatment of respiratory and soft tissue infections and sensitive intracellular pathogens such as chlamydia.
Highly active against b-haemolytic streptococci & S. pneumoniae.
Some activity against G-.
Topical, oral and IV preparations
acid-resistant coating when admined orally
penetration of many membranes, but not readily in brain or CNS. 1,5hr serum half-life
Metabolised in liver, excreted in bile & faeces
side-effects mainly include GI symptoms
Clarithromycin:
semi-synthetic macrolide
higher activity against certain pathogens
rapid biotransformation invivo to form active metabolite
used for acute upper + lower RTIs such as pharyngitis, sinusitis and against various STDs
bind irreversibly to 50s subunit and block entrance to ribosomal exit tunnel and cause growing peptide chain to dissociate from ribosome during translocation.
Generally bacteriostatic but can be cidal.
Azithromycin: An Azalide
Semi-synthetic macrolide
15-membered ring produces unique pharmacokinetics
prolonged tissue levels of around 50hrs
Improved effectiveness against Haemophilus influenzae. Also some single-dose treatment of some STIs. This along with erythromycin and clarithromycin are used first-line to treat whooping cough.
However cotrimoxazole is used when macrolides are contraindicated. Azithromycin is drug of choice in neonates.
Lincosamides: Lincomcin + Clindamycin
examples MOA spectrum of activity clinical uses adverse effects
Lincomycin + Clindamycin
Lincomycin is product of Streptomyces Lincolnensis
Clindamycin:
semi-synthetic derivative with better activity and absorption.
binds to 50s ribosome and interfers with peptide elongation by causing dissociaition of peptidyl-tRNA from ribosome. It also facilitates opsonisation, phagocytosis and intracellular killing of bacteria.
Active vs most anaerobes but not Clostridium difficile.
Active vs most aerobic G+ves. G-ve aerobes are resistant.
Clinical uses include bone and joint infections + abdominal sepsis. Topical clindamycin used for acne vulgaris.
Adverse effects include diarrhoea, can also cause pseudomembranous colitis by growth of c diff in gut.
Also nausea, anorexia, flatulence,
Streptogramins:
Background structure Admninistration MOA Uses
natural antibiotic isolated from streptomyces species.
each member of family consists of 2 antibiotics which are produced as synergic mixtures by streptomyces.
both components are structurally different. The chemically distinct groups are stretogramin A (type II) + streptogramin B (type I).
Example –> Quinupristin-Dalfopristin
A group = Dalfopristin
B group = Quinupristin
On their own, both are weak bacteriostatic, but in combination the effect is bactericidal.
Semisynthetic parenterally-administered streptogramin
quinupristin binds to 50s, dalfopristin binds tightly to 70s or 50s which causes conformational change and increases affinity constant of quinupristin for 50s.
Causes irreversible constriction of exit channel through which polypeptides are extruded.
Used against serious skin infections and against G+ cocci, has good antistaphylococcal activity.including MRSA, and against Streps.
Chloramphenicol:
Uses MOA Admin pharmacokinetics activity + uses adverse effects
Broad Spectrum
Binds reversibly to 50s
binds to peptidyl transferase enzyme to inhibit transfer of growing peptide chain to next amino acid occupying A site. May interfere with binding of lincosamides and/or macrolides which bind at/near same site.
generally bacteriostatic.
V. insoluble so oral and IV are in prodrug form.
metabolised by liver, excreted in inactive form (kidney)
well distributed in body
Broad activity –> most G+ + G- including anaerobes
chlamydia, rickettsia, thyphoid due to salmonellae, eye infections.
Can cause blood dyscrasias- depression of bone marrow- aplastic anaemia, can cause grey baby syndrome, teratogenesis
Tetracyclines:
Examples MOA Pharmacokinetic Uses Adverse effects New class of semi-synthetic tetracyclines
Oxytetracycline + tetracycline
Newer semi-synthetic drugs include doxycycline + minocycline. Have majorly different pharmacokinetic properties amongst them.
Enter sensitive bacterial cells by active transport processes. bind reversibly to 30s s/u. interfere with binding of aminoacyl tRNA so the appropriate amino acid cant be attached to its tRNA. This is mainly bacteriostatic.
Mainly oral administration
Ca, Mg + Al form insouluble chelates with tetracyclines.
Active vs most G+ves + G-ves, many intracellular species and antiprotozoan activity. Also useful against systemic infections such as Rickettsial infections and genitourinary infections –> chlamydia.
Relatively non-toxic but can cause nausea, vomiting, swollen tongue, grey-stained teeth
Glycylcyclines:
Tigecycline- for serious life-threatening infections.
activity against VRE and MRSA. Has modification and position 9 of ring D.
The oxazolidinones:
MOA
spectrum of activity
clinical use
side-effects
Newish class of chemical class of synthetic AA Linezolid was first to enter clinical use in 2000. Inhibits protein synthesis before formation of initiation complex. Prevents interaction of 50s subunit with mRNA and formymethionine tRNA. Linezolid interacts specifically with 23s rRNA (50s subunit) Active vs G+ cocci, especially VRE + MRSA, complicated skin and soft tissue inection MDR/XDR-TB cases.
side-effects: diarrhoea, headache, nausea, rash
Mupirocin
active vs staphylococci, streptococci, only used topically, used in eradication of nasal carriers of S. aureus.
Fusidic acid:
antistaphylococcal agent, penetrates tissue and bone, used to treat osteomyelitis and skin conditions.
