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Antibiotics: cell envelope, Lecture 28 Dr. Alvin Fox 1 Key Words Sterilization/disinfection/antisepsis Beta lactam Antibiotic Penicillins Selective toxicity Cephalosporins/cephamycins Bactericidal Monobactam Bacteriostatic Clavulinic acid Minimal inhibitory concentration (MIC) Penicillinase/beta lactamase Susceptibility testing Polymyxin B Penicillin binding proteins Daptomycin Autolysins Isoniazid Cycloserine Ethioniamide Bacitracin Ethambutol Vancomycin Resistance 2 STERILIZATION • All killed • non-selective 3 • autoclaving Sterilization – 121oC (heat/pressure) * Heat resistant materials • ethylene oxide – non heat resistant – Usually equipment – being replaced e.g. H2O2/free radicals • ultra-violet light – surfaces (e.g. operating rooms) not totally effective • gamma radiation – mainly food industry 4 Membrane filters pores bacteria 5 Disinfection • Liquids that kill bacteria – e.g. phenol based – too toxic for skin surfaces 6 Antiseptics • Topical (e.g. skin) – e.g. iodine or 70% alcohol – “reduce” bacterial load 7 ANTIBIOTICS • Selectively toxic for bacteria – bactericidal (killing) – bacteriostatic (growth inhibition) • minimize harm to patient 8 Antibiotics • damage structures – present in bacteria – not present in host 9 Antibiotics work together with the immune system 10 Minimal inhibitory concentration • lowest level stopping growth • e. g. zone of inhibition around a disk impregnated with antibiotic 11 • Antibiotics that inhibit cell wall biosynthesis are bactericidal • Without cell wall, osmotic pressure causes bacteria to burst 12 Cross-linking of peptidoglycan Old New 13 Peptidoglycan synthesis Cytoplasm Cell Membrane Cell wall undecaprenol sugar amino acid 14 Cycloserine Cytoplasm alanine (ala) analog - inhibits conversion L-ala to D-ala - inhibits formation of D-ala-D-ala X X sugar amino acid X X 15 Bacitracin • Inhibits dephosphorylation 16 TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane Cell wall undecaprenol P P 17 TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane Cell wall undecaprenol P P 18 TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane Cell wall undecaprenol P P 19 TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell wall Cell membrane undecaprenol P P 20 TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane Cell wall undecaprenol P P 21 TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane Cell wall undecaprenol P MINUS BACITRACIN 22 TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane Cell wall undecaprenol P P PLUS Bacitracin 23 Vancomycin Cell wall Vancomycin • binds to D-ala-D-ala • inhibits cross-linking 24 Beta lactam antibiotics • penicillins • cephalosporins/cephamycins • monobactams 25 β lactams •inhibit penicillin binding proteins Cell wall β lactam •stop cross-linking Active site of enzyme Penicillin binding protein 26 STRUCTURE OF PENICILLIN O S C NH CH O C CH N CH3 C CH CH3 COOH Site of penicillinase action. Breakage of the β lactam ring. 27 Attached to lactam ring • penicillins – 5 membered ring • Cephalosporins/cephamycins – 6 membered ring • monobactams – no second ring 28 Chemical modifications change biological activity • Early lactam antibiotics – inactive against Gram negative bacteria • no penetration of outer membrane 29 Resistance mechansims • Produce β lactamase (penicillinase) – destroys antibiotic • modified penicillin binding proteins – don’t bind antibiotic • modified porins – no internalization of antibiotic 30 Clavulinic acid • β lactam • binds strongly to β lactamases – inhibits activity • limited potency as antibiotic • used in conjunction with other β lactams 31 Polymyxin B • binds – lipid A – phospholipids • disrupts outer membrane, Gram negative bacteria • toxic to human cells 32 Daptomycin • Causes depolarization of bacterial cell membrane 33 Anti-tuberculosis drugs Isoniazid and Ethionamide - chemically related - blocks mycolic acid synthesis Ethambutol -blocks arabinogalactan synthesis Cycloserine 34