Antibiotics in the Environment: Natural and Anthropogenic Contributions. Julian Davies UBC,Vancouver

Transcription

1 Antibiotics in the Environment: Natural and Anthropogenic Contributions. Julian Davies UBC,Vancouver

2 THE PARVOME (THE UNIVERSE OF BIOACTIVE NATURAL PRODUCTS) uorigins: EVOLUTIONARILY VERY OLD. STRUCTURAL COMPONENTS FOUND IN METEORITES AND PRIMORDIAL SOUP REACTIONS ustructural DIVERSITY: (CHEMICAL) SPACE IS BIG. YOU JUST WON T BELIEVE HOW VASTLY, HUGELY, MIND- BOGGLINGLY BIG IT IS * ufunctions: INVOLVE MANY ASPECTS OF MICROBIAL PHYSIOLOGY, BEHAVIOUR AND MORPHOLOGY, INCLUDING CELL-CELL INTERACTIONS (POSITIVE AND NEGATIVE). umechanisms: FREQUENTLY (?) BASED ON SPECIFIC INTERACTIONS WITH MOLECULAR OR MACROMOLECULAR LIGANDS ANDSUBSEQUENT MODULATION OF TRANSCRIPTION. udistribution: UNIVERSAL. BEST CHARACTERISED IN BACTERIA, FUNGI, AND PLANTS. * DOUGLAS ADAMS THE HITCHIKERS GUIDE TO THE GALAXY

3 Antibiotics have multiple biological activities Recombination Horizontal gene transfer Mutation Metabolism Bacterial product Cell receptor Gene regulation Signalling Allosteric effects Swarming, motility, biofilms Antibiotic production Virulence functions, Phage production

4 Eukaryotic Receptors for Anti-infective Compounds Receptor Compound Cytochrome P 450. Rifampicin GABA. Quinolones, Carbapenems Glucocorticoid. Rifampicin Motilin Erythromycin NMDA.. Cycloserine Pregnane.. Rifampicin

5 Are antibiotics naturally antibiotics? Antibiotic-production by bacteria in nature and in the laboratory ENVIRONMENTAL Generation time: months Aeration: low Nutrients: variable Carbohydrate: limited Water: variable Temperature: 0-40 ph: 2-10 Product yield: µgrams PRODUCTION Generation time: hours Aeration: high *Nutrients: high and constant Carbohydrate: high Water: unlimited Temperature: ph: 6-8 Product yield: grams

6 *Some typical substrates used for productive fermentation! Molasses (blackstrap) Fish Meal (herring, anchovy) Citrus pulp Asparagus juice Cottonseed oil Malt extract Beef extract Bovine blood Pork liver Distillers solubles Hydrolysed rabbit fur

7 Classical Evolution (recombination, mutation, HGT) TWO ERAS OF EVOLUTION Anthropogenic Evolution (same genetic mechanisms, xenobiotic selection pressure) INDUSTRIAL REVOLUTION PETROLEUM,, FERTILIZERS, ANTIBIOTICS, ANTISEPTICS, BACTERICIDES (e.g. TRICLOSAN) INTENSE CHEMICAL MUTAGENESIS &SELECTION

8 Transmissable Multidrug Resistance FDA Office of New Drugs Adapted from Saga and Yamaguchi. (2009) JMAJ 52(2):

9 The evolution of new ß-lactamase enzymes Information provided by Karen Bush

10 Global spread of CTX-Ms Resistance to ceftazidime Endemic Outbreak

11 THE TRADE ROUTES OF THE CTX-M ENZYMES Hawkey and Jones, 2009

12 AND NOW FOR SOMETHING COMPLETELY DIFFERENT.. Nairn Falls, BC

13 Wastewater treatment: where the action is?

14 Genetic Reactors involved in Resistance Development Baquero et al, 2008 Therapeutic use Mixed Use Disposal Dispersal

15 Antimicrobials used in animal therapy/feed/agriculture/aquaculture. Aminoglycosides Beta-Lactams Chloramphenicol Fluoroquinolones, Quinolones Glycolipids Glycopeptides Ionophores Lincosamides Macrolides Nitrofurantoin Oxazolidinones Penicillins Peptides Spectinomycin Streptogramins Sulfonamides Tetracyclines Tiamulin Trimethoprim

16 FATES OF ANTIBIOTICS AND RESISTANCE GENES IN FOOD ANIMAL PRODUCTION SWINE: 2.8 X 10 8 CHICKENS: 4.6 X 10 8 CATTLE: 2.8 X 10 6 Chee-Sanford et al, 2008

17 Three connected antimicrobial ecosystems Environmental ecosystem: low resistance gene selection The Resistome ) Clinical ecosystem: High selection pressure Non-clinical ecosystem: medium selection pressure Adapted from Martinez (2009)

18 Evolution of resistance genes from the environment Natural Resistome and Subsistome [*quasi-resistance] Antibiotic or other selection pressures Mobile Element Heterologous Host Selective Pressures** Gene capture (integrases) Functional resistance phenotypes Gene transfer (phage, plasmid, DNA) (i) Mutations, over-expression (ii) Antibiotic, heavy metal, biocide, etc. *(biosynthesis, degradation, signalling, metabolism, regulation) **(these can change drastically in certain circumstances))

19 In Memorium Antibiotics and BigPharma

20 The Davies Lab Finding and finding-out about antibiotics