MICR20010 Lecture 8 2023.pptx

MICR20010 Lecture 8 Antibiotics Dr. Jennifer Mitchell Microbiology School of Biomolecular and Biomedical Science Lecture 7 • DNA • DNA replication • Gene structure – Transcription • Protein synthesis – Translation • • • • Antibiotics The Genetic Code Mutation Genetic Exchange Learning Outcome...

MICR20010 Lecture 8 Antibiotics Dr. Jennifer Mitchell Microbiology School of Biomolecular and Biomedical Science Lecture 7 • DNA • DNA replication • Gene structure – Transcription • Protein synthesis – Translation • • • • Antibiotics The Genetic Code Mutation Genetic Exchange Learning Outcomes • What is an antibiotic? • Role of agricultural practices in emergence of antibiotic resistance • Mechanisms of Action • Antibiotic resistance • Control against resistance • Immunisation • Vaccine What is an antibiotic? • A chemical that kills or inhibits the growth of microorganisms Role of agricultural practices in emergence of antibiotic resistance • Antibiotics used as growth promoters for intensive animal farming • Survey of beef and poultry sold in U.S. supermarkets found relatively high levels of antibiotic-resistant bacteria • Products from animals treated with antibiotics cannot be subsequently labelled as organic • Antibiotic-resistant strains of Salmonella are commonly isolated from minced beef. A ceftriaxoneresistant Salmonella strain was acquired by a 12year-old boy from cattle treated with this drug Citrus Stubborn Disease Spiroplasma citri, a phloem-restricted pathogenic mollicute Spray crops with erythromycin Glossary • Antibiotics - metabolic products of one microorganism that inhibit or kill other microorganisms • Antimicrobial drugs – synthetic drugs produced by chemical procedures in the laboratory • Bacteriocidal - kills the organism • Bacteriostatic – inhibits organism’s growth long enough for immune system to clear it • Narrow spectrum – only effective against specific groups of microbes • Broad spectrum - effective against a variety of grampositive and gram-negative bacteria • Selective toxicity - chemical being used should inhibit or kill the intended pathogen without seriously harming the host Mechanisms of Action 1. Cell Wall Active Agents a) β-lactams, e.g. penicillin, b) Cefotaxime affect cross-linking of peptidoglycan c) Glycopeptides, e.g. vancomycin, binds to peptide side chains of peptidoglycan and prevents cross linking β-lactam Antibiotics • Cell wall structure of Gram-positive (left) & Gram negative (right) bacteria (Microbiology, Walker, Saunders Press) β-lactams • β-lactams bind directly to transpeptidase enzyme and inhibit its function (cross linking of peptide side chains) • Glycopeptides bind to peptide side chains of NAM and prevent transpeptidase from cross linking Mechanisms of Action 2. Inhibition of nucleic acid synthesis a) Selective toxicity to microbial nucleic acid synthesis b) Quinolones, e.g. ciprofloxacin inhibits DNA gyrase and topoisomerase c) Rifampicin affects RNA polymerase d) Sulphonamides and trimethoprim (tetrahydrofolic acid synthesis) Bacterial DNA • One long, single, • circular molecule. • DNA gyrase supercoils DNA • DNA topoisomerase unwinds supercoiled DNA (during DNA replication) Transcription • Rifampicin Sulphonamides and trimethoprim • Inhibit enzymes involved in synthesis of DNA and RNA • Sulfonamides inhibit pteridine synthetase • Trimethoprim inhibits dihydrofolic acid reductase. • Combination of both = Co-trimoxazole Mechanism of Action 3. Inhibition of protein synthesis a) Bacteria: 50S and 30S ribosome subunits b) Human: 60S and 40S subunits c) Aminoglycosides, Tetracyclines and Macrolides inhibit translation Antibiotic Resistance Background • Inevitable given bio-evolution • Controllable • Major problem – developed world - hospitals – developing world - community Acquired Resistance to Antibacterials • Mutations on the chromosome • Plasmid Acquired resistance Mutations on Chromosome (Minority mechanism clinically) Mutations arise at rate 10-8-10-10 per cell division Examples includes resistance to: • Methicillin (β-lactam). Mutations in (transpeptidease enzymes (PBPs) allow it to function in presence of drug) • Rifampicin (RNA polymerase inhibitor) • Streptomycin (protein synthesis inhibitor) – mutation in 30S ribosomal subunit prevents drug binding. 1 in 1010 cells in E. coli Streptomycin Rifampicin X Features of plasmid-mediated antibiotic resistance • High level resistance • Often multiple, e.g. resistance to cephalosporins & aminoglycosides • Easily transferable to other species • Commonly code for inactivating enzymes Features of plasmid-mediated antibiotic resistance • Plasmids with multiple antibiotic resistance genes predominate within hospital bacteria • Antibiotic resistance genes existed before the era of antibiotic treatment but have become prevalent due to selective pressure. • Highlights bacterial adaptability. Acquired Antibiotic Resistance • Mutation – (e.g. drug resistance in tuberculosis) • Transformation/transposition – (e.g. Penicillin-resistant gonorrhea) • Conjugation – (e.g. multi-resistant shigella) Mechanisms of Antibacterial Resistance 1. Producing enzyme to inactivate or destroy the drug e.g. β-lactamase 2. Altering the target/receptor of the drug 3. Preventing entry of the drug into the cell or efflux of the drug from the cell Antibiotic Resistance • Mutation and plasmid acquisition occur normally in bacteria • Antibiotic presence just selects for cells that are resistant - it doesn’t force the cell to become resistant • Antibiotic misuse = nice environment for antibiotic resistant organism to take over (sensitive bugs are killed or inhibited) • 1/3rd of antibiotic prescriptions unnecessary • Poor patient compliance Control of Antibiotic Resistance • • • • • • Restrict: prescription only Rotation Animal use: reduce growth promoters Expertise: provide guidance Surveillance: local, national, global Infection Control: cleanliness, hand washing Immunisation against infection • Important in prevention of human and animal infection e.g. – MMR, influenza and meningitis vaccines for humans – Foot and Mouth virus vaccine; • Future vaccine for Mycobacterium bovis – – causes TB in cattle which can spread to humans via drinking unpasteurised milk – (Zoonosis: infection passed from animals to humans) Immunisation Immunisation = the process of inducing or providing immunity against infection artificially This may be either active or passive Vaccines Vaccine • A suspension of live attenuated or inactivated microorganisms or fractions thereof administered to induce immunity and thereby prevent infectious disease Vaccination • The term used to refer to the administration of any vaccine or toxin Live vaccine • Attenuated (weakened) agent Killed vaccine and toxoid Killed vaccine • Organism killed or inactivated by exposure to heat or chemicals Toxoid • toxin which has been modified by treatment with heat or chemicals so that it is no longer damaging(toxic) but it still produces immunity Partial or Subunit vaccines • Hepatitis B vaccine is a genetically engineered subunit vaccine comprising the hepatitis B coat (surface antigen) only. • Acellular pertussis vaccines are now available which include the pertussis toxin and various other components which are important in protection Immunisation • Active immunisation is the administration of a vaccine or a toxoid in order to stimulate the production of antibody or other immune responses • Passive immunisation is the administration of preformed antibodies in order to provide temporary immunity Further Reading • Microbiology and Introduction • Chapter 20 “Antimicrobial Drugs” • Chapter 18 “Practical Applications of Immunology” – Vaccine section