MIIM30011 2024 L16 - Antibiotics.pdf

 Antibiotics Lecture 15 Dr Sacha Pidot [email protected] www.pidotlab.com Lectures 16-18 Antibiotics Antibiotic resistance Antibiotic discovery and development Sources of information Papers! – “Antibiotics: past, present and future”, Curr Opin Chem...

 Antibiotics Lecture 15 Dr Sacha Pidot [email protected] www.pidotlab.com Lectures 16-18 Antibiotics Antibiotic resistance Antibiotic discovery and development Sources of information Papers! – “Antibiotics: past, present and future”, Curr Opin Chem Biol, 2019 - https://www.sciencedirect.com/science/article/pii/S1369527419300190 – “A brief history of antibiotics and select advances in their synthesis”, https://www.nature.com/articles/ja201762 – Antibiotics: from prehistory to the present day, https://academic.oup.com/jac/article/71/3/572/2364412  By the end of this lecture you should be able to: To understand the principles underlying: – the mechanism of action of antibiotics – the basis of selective toxicity To compare and contrast important features of different antibiotics within each mode of action group What are antibiotics? Molecules that kill, or stop the growth of, microorganisms, including bacteria, fungi or viruses Can be: Derived from nature (natural products) Synthetic (synthetic chemistry) Semi-synthetic (modified7 natural products)  Where do antibiotics come from? Chemical Nature Semi-synthesis synthesis Bacteria/Fungi Derived from Primarily natural product Lab made Actinomycetes https://www.army.mil/article/167237/army_scientists_synthesize_high_perf orming_energetic_material methicillin tetracycline fluoroquinolone  Natural product antibiotics >70% of antibiotics in the clinic are natural products or their derivatives Made by molecular assembly lines – Large gene clusters (can be >100 kb) – Large proteins (can be >ribosome!) – Small products Mike Bird/ Wikimedia Commons, https://commons.wikimedia.org/wiki/File:Manufacturing_line.jpg >40kb tylosin https://en.m.wikipedia.org/wiki/File:CallystatinA-modular.jpg >1.4MDa MW 916 Da  Classifying antibiotics Bactericidal vs bacteriostatic – Bactericidal = kills – Bacteriostatic = inhibits growth https://commons.wikimedia.org/wiki/File:Bacteriostatic_agent_and_bactericidal_agent_-_en.png Broad vs narrow spectrum – Broad = both G+ve and G-ve – Narrow = either G+ve or G-ve  The ideal antibiotic Irreversible binding to a bacteria-specific target that results in bacterial cell death – i.e. acts on a target that is not present in humans – Can penetrate Gram negative and Gram positive cell walls Activity at very low concentration No drug-drug interactions Broad spectrum High oral availability Good tissue penetration – i.e. same concentration at all body sites Limited ability for resistance to develop Very few antibiotics fit all of these criteria!!  Where do they act? https://commons.wikimedia.org/wiki/File:Antibiotic_resistance_mechanisms.jpg Antibiotics targeting the cell wall  The bacterial cell wall https://commons.wikimedia.org/wiki/File:Figure_22_02_08f.png  Structure of peptidoglycan (NAM) (NAG) E. coli S. aureus L-Ala L-Ala D-Glu D-Glu meso-DAP L-Lys D-Ala D-Ala D-Ala Oligopeptide chains made of L- and D-amino acids link NAM and NAG https://commons.wikimedia.org/wiki/File:Peptidoglycan-membrane.png  Peptidoglycan crosslinking S. aureus + -gly-gly-gly-gly-gly gly-gly-gly-gly-gly + Transpeptidase (aka PBP) S. aureus  A tale of two antibiotic classes Beta-lactams Glycopeptides Penicillin Vancomycin – Cephalosporins Teicoplanin – Carbapenems – Monobactams Bactericidal G+ve activity Bactericidal G+ve and G-ve activity Penicillin Vancomycin  Penicillin vs vancomycin: where do they come from? Penicillin Vancomycin – Fungi! – Amycolatopsis orientalis Alexander Fleming Soil screening – 1928 – 1954 https://www.dsmz.de/collection/catalogue/details/culture/DSM-40040  Penicillin: mode of action Penicillin DD-transpeptidase (Penicillin binding protein, PBP) With penicillin No penicillin End result is increased osmotic pressure → lysis → death https://upload.wikimedia.org/wikipedia/commons/thumb/d/d0/Penicillin_inhibition.svg/255px-Penicillin_inhibition.svg.png  Vancomycin: mode of action Vancomycin Binds D-Ala-D-Ala end of stem peptide End result is increased osmotic pressure → lysis → death https://en.wikipedia.org/wiki/File:Vancomycin_resistance.svg  Penicillin vs vancomycin: resistance Penicillin Vancomycin Beta-lactamase production Change terminal D-Ala-D- Ala residue Overcome with beta- lactamase inhibitors Cannot be overcome as yet  Other beta-lactams Other beta-lactams – Cephalosporins 4 generations Difference spectrum of activity to penicillin Less susceptible to beta-lactamases – Monobactams Narrow spectrum – only G-ve bacteria – Carbapenems Broad spectrum – used mainly for MDR bacteria https://www.ringbio.com/press-release/introduction-of-beta-lactams-antibiotics Antibiotics targeting the ribosome  The bacterial ribosome 50S 30S 26  Bacterial protein synthesis inhibitors Many antibiotics act on the ribosome Tetracyclines 30S subunit Aminoglycosides Linezolid Chloramphenicols 50S subunit Macrolides Majority are natural products – suggests that 27 the ribosome is a great target!  A tale of two antibiotic classes Tetracyclines Oxazolidinones Tetracycline Linezolid – Doxycycline, minocycline, tigecycline Bacteriostatic G+ve activity Bacteriostatic – “Reserve antibiotic” G+ve and G-ve activity – Expensive!  Tetracycline vs linezolid: where do they come from? Tetracycline Linezolid – Streptomyces – Synthetic aureofaciens (chlortetracycline) Upjohn (Pfizer) – Discovered mid 1990s Lederle labs – Approved 2000 – Patent issued 1953 – Commercial use 1978  Tetracycline: mode of action Tetracycline 30S ribosomal subunit – Prevent amino-acyl tRNA binding to A site http://www.antibiotics-info.org/tetracycline.html End result is inhibited protein production  Linezolid: mode of action Linezolid 50S ribosomal subunit – Blocks P-site and stops initiation of protein biosynthesis http://www.antibiotics-info.org/linezolid.html End result is inhibited protein production  Tetracyclines vs linezolid: resistance Tetracycline Linezolid Ribosomal methylation Very low levels Efflux –