Bacterial Infections Flashcards
What is the main bacterial cause of syphilis?
Spirochaete bacterium- Treponema pallidum
What did Paul Ehrlich receive a nobel prize for?
Investigated cure for sleeping sickness, but product he developed caused blindness. One of the compounds he synthesised actually cured syphilis and later derived neosalvarsan.
What is salvarsan?
Prodrug that metabolises to give oxophenarsine, used clinically against syphilis in 1930s. Reacts with protein thiol groups causing denaturation.
Describe the mechanism of action of beta lactams.
Inhibit cell wall synthesis in bacteria causing lysis. Enzymes responsible for forming crosslinks form covalent bonds with beta-lactam ring.
What are the three amino acids that penicillin is based on?
Phenylalanine
Cysteine
Valine
What does beta-lactam activity depend on?
Ability to penetrate cell wall
Resistance to beta-lactamases
Affinity of transpeptidases
Resistance to stomach acid
What are semi synthetic penicillins derived from?
6-aminopenicillanic acid
Why is penicillin G difficult to synthesise?
Requires 90 degree bond angles in the lactam ring
Describe the disadvantages of penicillin G.
Sensitive to beta-lactamases
Acid labile
Not given orally
Which beta-lactam is resistant to class I beta-lactamases?
Amoxicillin
Which beta-lactams are resistant to all beta-lactamases?
Flucloxacillin
Methicillin
What are celphasporins?
Beta lactams
2nd generation used in gram -ve infections
3rd generation used in serious gram -ve infections
What are carbapenems?
Broad spectrum beta-lactams with high incidence of resistance.
What is vancomycin?
Aminoglycoside, monobactam class. Used in serious gram +ve infections, not taken orally.
Describe the three types of ribosomal imaging that won the 2009 nobel prize.
Ramikrishnan- 30s subunit from Thermus thermophilis
Steitz- 50s subunit of Halocura marismortui
Yonath- drug ribosome structures in Deinococcus radiodurans
What are the features of tetracyclines?
Biosynthesised from acetate by Streptomyces.
Broad spectrum antibiotic with resistance being mostly membrane associated.
Work via inhibition of EFTu binding
Why are tetracyclines contraindicated in children?
Stain growing tooth enamel.
How do aminoglycosides work?
Cause misfunctioning of ribosomes by binding of aminoacyl-tRNA to the ribosomal A site. Especially active against gram -ve bacteria.
What is a disadvantage of aminoglycosides?
Often cause nephrotoxicity. Due to their chiral centres, they are hard to alter.
What is linezolid?
An oxazolidinone, works by inhibiting ribosome function. Active in MRSA and hospital acquired gram +ve infections. Toxic to 70s ribosomes.
What features of the structure of linezolid are advantageous?
Electron donating nitrogen improves its safety profile.
N-aryl group is required for activity.
Describe the original structure of erythromycin.
Derived from Saccharopolyspora erythema, originally existed of a mixture of closely related compounds, A and B. Around 90% of the mixture was the active erythromycin A.
What is erythromycin?
A macrolide, blocks the ribosomal exit tunnel in bacteria.
What are the disadvantages of erythromycin?
Foul tasting and extremely difficult to taste mask.
What makes telithromycin more active than erythromycin?
As a second generation ketolidem it is able to over come RNA ribosomal modification and is more hydrophobic and stable.
What is the complication of using chloramphenicol internally?
Aplastic anaemia
Describe the structural features of chloramphenicol.
Two chiral centres but only has one active isomer out of four. Combats growth of both gram +ve and -ve bacteria.
What are lincosamides?
Same action as macrolide, blocking the ribosomal exit tunnel. Used in anaerobic and protozoan infections such as TSS.
What is the method of action of fusidic acid?
Binds to EFG in GTP form, binding to the ribosome as normal, GTP is then hydrolysed preventing the removal of EFG from the ribosome.
Describe the action of quinolones.
Block a subunit of DNA gyrate, preventing the supercoiling of bacterial DNA. Broad spectrum and are active against penicillin resistant gram -ve infections.
What is Nalidixic acid used in?
Quinolone with minimal serum levels used in uncomplicated urinary tract infections.
What is ciprofloxacin used for?
Due to it being a fluoroquinolone, the increased electronegativity gives higher gram +ve and systemic activity. Used in respiratory tract infections and gonorrhoea, prophylaxis of M. meningitis and anthrax.
What are the contraindications of ciprofloxacin?
Not used in children due to damaging tissues such as tendons.
Severe CNS effects when used with NSAIDs.
What is levofloxacin?
Quinolone used in Streptococci infections
What is levofloxacin derived from?
First generation quinolone, ofloxacin, with double the potency.
When are nitrofurans used?
Broad spectrum urinary tract infections
What environment do nitrofurans require?
Anaerobic- radical anions extract H from DNA causing cleavage of sugar-phosphate backbone.
What is metronidazole used for? How?
Treatment of C. difficile infections using radical anions to extract H from DNA causing cleavage of sugar-phosphate backbone. Also treats helicobacter and protozoal infections.
What is the main side effect of metronidazole?
Alcohol intolerance.
How is C. difficile infection acquired?
Administration of broad spectrum antibiotics eliminates commensal microflora, thus allowing its proliferation.
How was sulphanilamide first discovered?
Prontosil was tested as a treatment for Staphylococcal septicaemia by Domagk. Trefouel proved that this was a prodrug for sulphanilamide.
How was the foul taste of sulphanilamide first masked?
With diethylene glycol solvent which was found to be extremely toxic.
How does sulphanilamide work?
Mimics para-aminobenzoic acid in the metabolism of folate by inhibiting dihydroperoate synthetase. Not active against serious disease.
What is sulphadiazine used for?
Treatment of bacterial infection, malaria, cancer and rheumatoid arthritis. 100x more active that sulphanilamide, it is 75% ionized at pH 7.4.
What is the mechanism of action of trimethoprim?
Inhibits dihydrofolate reductase in folate metabolism. Doesn’t affect mammalian folate as its affinity for the bacterial enzyme is 5000x more than for the mammalian enzyme.
What are substituted sulphanilamide used for?
Active against Gram-positive bacteria, including pneumococci and meningococci. Largely superseded by penicillins.
Describe the required structure for sulphanilamides.
Sulfonamide group is required and optimum acidic pKa of the sulfonamide group for antibacterial activity is 6-7
Sulfonamide nitrogen must be SECONDARY
Aromatic ring is required and must be para-substituted with a para-amino group
What are trimethoprim combinations used for?
Urinary tract infections, typhoid fever, chronic bronchitis, gonorrhoea in penicillin resistant patients
Describe the structural uses of pyrimethamine.
Chlorophenyl ring makes it more hydrophobic than trimethoprim.
Gets taken up into cells, but is too hydrophobic and gets stuck in bacterial cell walls
What is pyrimethamine used for?
It is a dihydrofolate reductase inhibitor used in protozoa and as an antimalarial.
Describe the structural uses of methotrexate.
Pteridine ring gives DHFR activity
Glutamate (POLAR) side chain for active transport by an amino acid carrier
What is methotrexate used for?
Targets mammalian DHFR.
Anticancer in rapidly proliferating tumours
At low doses in IBD, rheumatoid arthritis and ectopic pregnancy.
What is the disadvantage of using penicillin and methotrexate concomitantly?
Penicillin inhibits elimination of methotrexate making toxic effects more likely.
What is the cause of TB?
Mycobacterium tuberculosis
What are the symptoms of TB?
Mainly respiratory
90% of infected are asymptomatic and don’t transmit the disease
What are the targets for TB treatment?
Mycobacteria have a cell wall rich in mycolic acids.
What is streptomycin? How does it work?
First developed antibiotic cure for TB, actively transported into cells to inhibit ribosome function. Must be given IM and resistance is common.
What is isoniazid? How does it act?
Prodrug for isonicotinamide, resembling NADH thus inhibiting desaturate in mycolic acid synthesis in TB. Highly active in rapidly dividing strains but not used alone due to resistance.
What is the action rifamycins? What are they derived from?
Inhibit RNA polymerase by binding the the beta subunit, preventing nucleotide dimers from forming complexes with another nucleotide. Biosynthesised by Amycolatopsis mediterranei.
What are rifamycins used for?
First line therapy for treatment of TB.
What is the action of ethambutol?
Inhibits arabinogalactan synthesis via arabinosyl transferase, preventing cell wall formation in TB.
What is a complication of ethambutol use?
Optic neuritis.
What is the action of pyrazinamide? What is it used for?
Prodrug converted to pyrazinoic acid in TB by pyraziniamidase. Can be used for TB treatment in pregnancy.
What is cycloserine?
TB treatment that inhibits alanine racemes and alanine ligase.
What are meningococci?
Gram negative diplococci with 12 antigenically different capsular groups.
Which menigococcal capsular group accounts for the most cases of meningococcal disease?
Meningococcal B
What is the leading cause of community acquired pneumonia in adults?
Streptococcus pneumoniae
How many pneumococcal subtypes are there?
Over 90 but only 7-10 considered pathogenic.
What is Haemophilus influenzae?
Bacteria with 6 capsular serotypes, B being the most prevalent strain before vaccine was introduced.
