Treatment of bacterial infections Flashcards
What is an antibiotic?
Derived from microorganisms.
Can be broad or narrow spectrum.
Semisynthetic?
Chemical modification of antibiotics.
Synthetic?
Chemically synthesised in the lab (antibacterical).
What are the 4 key mechanisms of antibiotic action?
Inhibit bacterial cell well.
Inhibit bacterial DNA synthesis.
Inhibit bacterial protein synthesis.
Act as antimetabolites.
Staphylococcal aureus?
Gram +ve.
Grow in grape like clusters on skin and responsible for wound infections.
MRSA.
Streptococcal pneumoniae.
Gram +ve.
Grow in chain like clusters.
Cause pneumonia and meningitis.
Escherichia coli
Gram -ve.
Rod like
Many urinary tract infections.
Haemophilus influenzeae
Gram -ve.
Vaccination about HiB but other forms cause respiratory tract/ear infections.
Explain gram positive bacteria.
Peptidoglycan cell wall ~ 30nm
= thick, interacts with gram stain.
Plasma membrane.
Explain gram negative bacteria.
Outer membrane (protective) with water filled 'porin' channels. Proteins joining outer membrance to peptidoglycan (~3nm) across periplasmic space. Inner plasma membrane.
Stains poorly - thick outer membrane where stain can’t get through and then very thin peptidoglycan therefore takes up little stain.
Explain the bacterial peptidoglycan cell wall.
N-acetylmuramic acid (NAMA) and N-acetylglucosamine (NAG) are linked via sugar residues.
NAMA and NAMA peptide side chains are linked by amide linkage.
Explain the formation of the peptidoglycan cell wall.
NAMA, NAG and amide linkage (building blocks) are formed inside the cell and transported across the plasma membrane attached to a lipid transporter.
Released and linked to each other by TRANSGLYCOSYLASE enzyme into a linear strand.
Linear strand are crossed linked by TRANSPEPTIDASE.
Lipid transporter returns to the cell interior.
Explain the general inhibition of the cell wall production.
B-lactam antibiotics (bacteriocidal)
- penicillins, cephalosporins, carbapenems, monobactams.
They prevent the amide bonds forming between NAMA peptide side chains by inhibiting transpeptidase and transglycosylase.
Explain the structure of B lactam.
4 ring structure - highly reactive and interacts with transglycosylase and transpeptidase…therefore NO CELL WALL FORMATION.
What is the effect of changing th side chains of B lactam?
Alter…
…oral bioavailability (stability in stomach acid/interactions with food)
…susceptibility to B-lactamase
…spectrum of activity.
What is clavulanic acid?
Inhibits many forms of B-lactamase.
What is B-lactamase?
Destroys the B-lactam rings - doesn’t interact with and inhibit enzymes - cell wall is still produced.
Benzyl penicillin?
Pencillin antibiotic.
Pen G.
Broad spectrum, gram -ve, not orally active, susceptible to B-lactamase.
Methicillin?
Penicillin antibiotic - resistant to Blactamase but by other methods. Not orally active. nephrotoxic.
Axmocillin.
Penicillin antibiotic - administered with clavulanic acid - co-amoxiclav.
Name a cephalosporin antibiotic.
Cefalexin. Good for gram +ve not -ve, susceptible to B-lactamase.
Side effects of b-lactams?
Upset the gut flora - GI disturbances
Hypersensitivity reactions; rash - anaphylatic shock.
Convulsions if given intrathecally.
Name 3 other antibacterials that interfere with the cell wall production.
Cycloserine - prevent NAMA side chain formation
Vancomycin - inhibit release of cell wall building block from lipid transporter (good for +ve).
Bacitracin - prevent recycling of lipid transporter.
Explain the inhibition of DNA synthesis.
By Fluroquinolones eg ciprofloxacin.
Inhibit the folding of DNA by DNA gyrase
Good for +ve and -ve, orally active
BUT - doesn’t cross BBB, antacids prevent absorption from gut.
Explain how you would inhibit protein synthesis.
The structure and size of ribosomes are different.
Human: 40S and 60S.
Bacteria: 50S (where transpeptidation occurs) and 30S (3 binding sites for DNA).
Explain aminoglycosides.
Streptomycin.
Bacteriocidal.
Causes misreading of the 30S sunbunit
Good against aerobic gram -ve bacteria. Transported across the cell wall by an O2 dependent transporter (which can be blocked by chloromephenicol).
Causes nephro and ototoxicity.
Explain tetracyclines?
Doxycycline.
Compete with tRNA for codon on mRNA 30S.
Broad spectrum - bacteriostatic - resistance is a problem.
Orally active but forms insoluble complexes with Ca++ and iron.
GI upset.
Explain chloramphenicol
Inhibits transpeptidation.
Broad spectrum, bacteriostatic, resistance is problem
Idiosyncratic bone marrow supression
Used in eye drops to treat bacterial conjunctivitis,
Explain macrolides.
Erythromycin. Inhibits translocation of the risbosome along the mRNA.
Bacteriostatic.
What are antimetabolites?
Chemicals that inhibit the use of a metabolite.
How do bacteria synthesis folate and then use it for DNA synthesis?
PABA –dihydropteroate synthase–>folate–dihydrofolate reductase–>tetrahydrofolate… DNA synthesis.
Explain sulfonamides.
Sulfanilamide
Analogues of PABA - compeitive inhbitor of dihydropteroate synthase.
Bacteriostatic
Orally active - corss the BB, metabolised in the liver.
Trimethoprim?
Inhibit DHFR
1000x more potent in bacteria.
Explain the drug treatment of TB caused by mycobacterium tuberculosis.
Thick lipid rich, waxy cell wall (not g+/-ve).
Rifampicin - combinations, for a long time.
Explain resistance.
Resistance occurs to spontaneous mutations that anable the bacteria to withstand the deletrious effects of the drugs…and bacteria have high replication rates, mutations occur more frequently
Resistant genes = plasmids - easily passed between bacteria.
Plasmid genes can act as transposons - jump from plasmid DNA to chromosomal DNA and back…spread resistance.
What are the 6 main ways that resistance occurs?
1) Metabolic bypass - alternative means of producing folic acid.
2) Target overproduction - excessive production of PBPs - outcompete penicillin.
3) Active excretion of antibacterial from inside bacteria - resistance to tetracyclines and erythromycin.
4) Reduced entry of antibacterial across cell wall - mutation in porins?
5) Destruction or inactivation of the antibacterial (B-lactamase)
6) Mutations in target molecules to make them less sensitive to anitbiotics - vancomycin resistance
How can you decrease the development of resistant strains?
1) Decrease inaapropriate use of antibiotics
2) Limit key antibiotics
3) Use antibiotics in rotations/combinations
4) Avoid prophylaxis in animal feed stuff.
