W4 Antibiotics The ß-lactam antibiotics: the Penicillins Comprised of the beta lactam ring + thiazolidine ring= penem core (look back at 1st year notes) ß-lactam antibiotics: clinical usage · URTI (e.g. tonsilitis) · LRTI (e.g. pneumonia) · STI (e.g. gonorrhoea, syphilis) · Skin and tissue infections (there may be hypersensitivity and anaphylactic shock in some patients; alternative antibiotic warranted) Antibiotic usage worldwide · An estimated 10,000 metric tons of antimicrobial agents are manufactured worldwide per year · The ß-lactam antibiotics include: o Cephalosporins (30%) o Penicillins (7%) Other beta lactams (15%) - tetracyclines, aminoglycosides and all other antimicrobial drugs How do antibiotics work? DNA gyrase The Quinolones · George Lesher, 1962 · Used for UTI · 10,000 analogues · 6 FDA approved · 24% worlds manufactured antibiotics · Synthetic antibacterial compounds · DNA gyrase inhibitors . Found in all bacteria therefore broad spectrum (G +/-) · Derivatives of nalidixic acid (fluorinated) o Ciprofloxacin and moxifloxacin are fluoroquinolones · Quinoline backbone · Functional R-group Mechanism of action · Quinolone antibiotics interfere with changes in DNA supercoiling by binding to DNA gyrase (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. . This toxicity doesn't occur with our DNA because our DNA replication is different to bacteria Clinical usage: · UTIs . MDR infections · Pyelonephritis · Prostatitis · Pneumonia · ffighly restricted use in children un UK (anthrax or CF pulmonary infection)-musculoskeletal side effects PROTEIN STYNTHESIS (50S inhibitors) the macrolides · 1952- erythromycin from Streptomyces erythraeus · Natural products- polyketides . 20% world's manufactured antibiotics · Macrocyclic lactone ring . Mostly G+ (limited G-) considered broad spectrum · Most active against G+ cocci (mainly staph and step cocci) · Macrolides are also active against mycobacteria, mycoplasma, ureaplamsa, spirochetes and other organisms. · Examples include: o Erythromycin o Azithromycin o Clarithromycin o Telithromycin o Cethromycin Mode of action · Protein synthesis inhibitors · Reversible binding to the P site on 50S ribosomal subunit o Arrest the translation activity of bacterial ribosome · Bacteriostatic
W4 o Distribution of proteome Stops protein production (disrupts the proteome) · leading to cell death · Are not covalently bonded although have a high affinity- can be reused Nascent polypeptide chain A site 50S P site Xiaa Transferase site Macrolides IRNA mRNA template 30S Clinical usage · Gram positive infections o Streptococci o Pneumococci o Staphylococci o Enterococci o Chlamydia o Mycobacteria · Gram negative infections o Bordetella pertussis o Haemophilus influenzae PROTEIN SYNTHEIS (30S INHIBITORS) TffE AMINOGLYCOSIDASES · natural products- amino sugars bonded by glycosidic bonds · 1944- Waksman and Schatz · Streptomycin from Streptomyces griseus · Bactericidal (aerobic G-) · Mostly G- bacteria (not anaerobes) (+mycobacteria) o Streptomycin o Kanamycin o Tobramycin o Gentamycin o Neomycin Mechanism of action · Protein synthesis inhibitors . Bind to the aminoacyl site of 16S rRNA in 30S subunit of the ribosome (irreversible) . Cause mis-incorporation