ANTIBIOTICS WHAT ARE ANTIBIOTICS . Chemical compounds used to treat infections caused primarily by bacteria; they must be sufficiently non-toxic to be given to infected host - 'selective poisons' · Used to supplement body's natural defences by either killing (bactericidal) or inhibiting (bacteriostatic) CLASSIFICATION OF ANTIBIOTICS - Classified on their chemical / biosynthetic origin · Natural antibiotics = produced naturally by fungi / bacteria (e.g. penicillin) · Semi-synthetic antibiotics = chemically modified natural antibiotics (e.g. ampicillin) · Totally synthetic antibiotics = manufactured (e.g. trimethoprim) They are also clustered within large groups called antimicrobials or chemotherapeutic agents WORLDWIDE ANTIBIOTIC USAGE · Estimated 10,000 tons of antimicrobial agents are produced worldwide every year · Beta-lactams = 52% - includes cephalolospornins (30%), penicillins (7%) and other beta- lactams (15%) · Fluoroquinolone = 24% · Macrolide = 20% WHAT DO ANTIBIOTICS TARGET? · The cell wall synthesis - sufficiently different to our cell membranes to target · Nucleic acid synthesis - subtle differences in the enzymes required in bacterial DNA/RNA than in our cells · Protein synthesis · Metabolism - they make folic acid unlike us USING THE CELL WALL AS A TARGET (BETA-LACTAM ANTIBIOTICS) · Penicillin = beta-lactam ring and a thiazolidine ring - penem core (part which needs to stay intact) 1 S 5 NH -NH 3 · Penicillium chrysogenum produced penicillin G when grew in phenyl acetic acid however it was not stable in acidic conditions - couldn't be taken orally · When the same fungus was grown in phenoxy acetic acid it produced penicillin V which was acid stable - Florey and Chain won a Nobel prize for this optimisation of penicillin · Dorothy Hodgkin won a Nobel prize for deciphering the beta-lactam nucleus structure using x- ray crystallography . Amoxicillin and methicillin are improved semi synthetic versions of penicillin How do they work? · Inhibit transpeptidase . Transpeptidase is used to build the crosslinks between NAM and NAG repeating subunits . Penicillin core is an analogue of the terminal D-ala D-ala cross link therefore when present it forms a covalent bond with transpeptidase and stops it from working · Competitive inhibition - irreversible binding · Beta-lactamases can break open and destroy the beta-lactam core, rendering the antibiotic useless Clinical usage - broad spectrum · URTI (e.g. tonsilitis) · LRTI (e.g. pneumonia) · STI (e.g. gonorrhoea, syphillis)
· Skin and tissue infections - Hypersensitivity and anaphylactic shock in some patients - alternative antibiotics warranted USING NUCLEIC ACID SYNTHESIS AS A TARGET - QUINOLONE · DNA gyrase inhibitors · Found in 1962 by George Lesher · Predominantly used for UTI's · 10,000 analogues made - only 6 FDA approved for use in humans . 24% of worlds manufactured antibiotics · Synthetic · Found in all bacteria therefore broad spectrum (gram +ive and -ive) · Derivatives of nalidixic acid (fluorinated) · Quinoline backbone - two benzene structures in the core · Functional R-group Mechanism of action . They interfere with DNA supercoiling by binding to DNA gyrase (topoisomerase Il in first and