Antimicrobial resistance III_240614_140304.pdf

Antimicrobial resistance Samanthika Jagoda, BVSc (Perad), MVM (Massey), PhD (Tokyo) All images in these slides are from public domain and this academic presentation will only be used for the purpose of teaching 2nd year undergraduates in a public university ...

Antimicrobial resistance Samanthika Jagoda, BVSc (Perad), MVM (Massey), PhD (Tokyo) All images in these slides are from public domain and this academic presentation will only be used for the purpose of teaching 2nd year undergraduates in a public university  Subtopics Antimicrobial agents Bacterial resistance to antimicrobial drugs Antimicrobial susceptibility testing  Objectives By the end of the module, students will be able to: 1. identify bacterial resistance mechanisms for resisting antimicrobial agents 2. discuss the molecular basis for bacterial antimicrobial resistance 3. explain laboratory methods for detecting and measuring antimicrobial resistance Antimicrobial agents  At around 1550 B.C., Egyptians used honey for wound dressing. Honey contains hydrogen peroxide which can kill bacteria More than 2,000 years ago, moldy bread was used in China as a treatment for infected wounds Image courtesy: https://amrls.umn.edu/antimicrobial-resistance-learning-site  Alexander Fleming When I woke up just after dawn on September 28, 1928, I certainly didn’t plan to revolutionize all medicine by discovering the world’s first antibiotic, or bacteria killer. But I guess that was exactly what I did.”  ANTIBIOTIC A low molecular substance produced by a microorganism that at a low concentration inhibits or kills other microorganisms  ANTIMICROBIAL AGENTS Any substance of natural, semisynthetic or synthetic origin that kills or inhibits the growth of microorganisms but causes little or no damage to the host  Antimicrobial agents = antibiotics + synthetic compounds with antimicrobial activity  Therapeutic use of antimicrobial agents depend on their selective toxicity - kill or inhibit bacterial pathogens BUT - no direct toxicity for animals/humans receiving treatment Antimicrobial discovery timeline Antimicrobials can be classified based on: Effect on bacteria Spectrum of activity Mode of action Effect on bacteria Image courtesy: https://amrls.umn.edu/antimicrobial-resistance-learning-site  EFFECT ON BACTERIA Bactericidal drugs Kill target bacteria e.g aminoglycosides, cephalosporins, penicillins, and quinolones Bacteriostatic drugs Inhibit or delay bacterial growth and replication e.g tetracyclines, sulfonamides, and macrolides SPECTRUM OF ACTIVITY Image courtesy: https://amrls.umn.edu/antimicrobial-resistance-learning-site  SPECTRUM OF ACTIVITY Narrow spectrum antibiotics Broad spectrum antibiotics Have limited activity Active against many species Only useful against of bacteria (both Gram- particular species of positive and Gram-negative) microorganisms E.g tetracycline chloramphenicol E.g vancomycin only fluoroquinolones effective against Gram- positive bacteria polymixins only effective against Gram negative bacteria  MODES OF ACTION Inhibit bacterial cell wall synthesis e.g penicillins, cephalosporins Inhibit protein synthesis e.g aminoglycocides tetracyclines macrolides nitrofurantoin chloramphenicol  Inhibition of cell membrane function e.g polymixin, colistin  Inhibit nucleic acid synthesis e.g quinolones, novobiocin, rifampin, sulphonamides, trimethoprim Disruption of DNA structure and inhibition of DNA repair e.g Metranidazole Modes and sites of action of antimicrobial drugs  Antibiotic usage in animals Therapeutic – to treat clinically ill animals Prophylactic and metaphylactic Growth promotion Image courtesy: https://amrls.umn.edu/antimicrobial-resistance-learning-site Bacterial resistance to antibacterial drugs  Antimicrobial resistance is the ability of a microorganism to survive and multiply in the presence of an antimicrobial agent that would normally inhibit or kill this particular kind of organism  Fleming’s Nobel lecture in 1945 “It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them. The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant. E.g. Mr. X. has a sore throat. He buys some penicillin and gives himself, not enough to kill the streptococci but enough to educate them to resist penicillin. He then infects his wife. Mrs. X gets pneumonia and is treated with penicillin. As the streptococci are now resistant to penicillin the treatment fails. Mrs. X dies”.  What is the Burden of AMR? If Nothing is done now Approx. 10 Million deaths by 2050 attributable to Current global estimates of AMR AMR-related deaths = 700 000 Global economic loss up to US$ 100 trillion  Bacterial resistance strategies To survive in the presence of an antibiotic, modes of action of antibiotics must be counter-acted by bacteria  Strategy 1 : Preventing access Prevent the antimicrobial from reaching its target by reducing its ability to penetrate the cell (by modifying cell membrane porin channels) e.g Pseudomonas aeruginosa against imipenem Many Gram negative bacteria against aminoglycosides Image courtesy: https://amrls.umn.edu/antimicrobial-resistance-learning-site Strategy 2 : Eliminating antimicrobial agents from the cell via efflux pumps Some bacteria have membrane proteins that act as an export or efflux pump e.g E.coli and other Enterobacteriaceae against tetracyclines Image courtesy: https://amrls.umn.edu/antimicrobial-resistance-learning-site Strategy 3 : Inactivation of antimicrobial agents via modification or degradation Destroy the active component of the antimicrobial agent e.g Hydrolic deactivation of the beta-lactum ring in penicillins by beta lactamase Inactivated penicilloic acid can not bind to penicllin binding proteins Image courtesy: https://amrls.umn.edu/antimicrobial-resistance-learning-site Strategy 4 : modification of the antimicrobial target Some resistant bacteria reprogramme target sites to avoid recognition e.g Mycobacterium spp against Streptomycin (Modification of ribosomal proteins) Image courtesy: https://amrls.umn.edu/antimicrobial-resistance-learning-site Molecular mechanisms of resistance The abilities of bacterial organisms to resist antimicrobial compounds are all genetically encoded Two types of resistance in bacteria Innate (intrinsic) Acquired (extrinsic) Naturally coded and A microorganism expressed by all strains obtains the ability to of that particular resist the activity of a bacterial species particular antimicrobial agent to which it was e.g Gram negative previously susceptible bacteria are naturally resistant to vancomycin Not present in the entire species but only within certain strains  Acquired resistance Can result from: 1. Mutation 2. Acquisition of foreign genes through horizontal gene transfer  Horizontal Gene Transfer Process of exchanging genetic material between neighboring bacteria Occur via three main mechanisms 1. Conjugation 2. Transduction 3. Transformation Image courtesy: https://amrls.umn.edu/antimicrobial-resistance-learning-site Image courtesy: https://amrls.umn.edu/antimicrobial-resistance-learning-site  Many of the antibiotic resistance genes are carried on plasmids, transposons or integrons Integrons Mobile genetic elements Can capture and carry genes encoding antimicrobial resistance Contain integrase required for integration of its DNA into chromosome or plasmid Contain a promoter for expression of genes carried on the gene cassette Transposons Short, mobile sequences of DNA that can move as a single unit Contain the gene for a transposase enzyme and genes encoding antimicrobial resistance Transposase enzyme is needed to incorporate transposon in to a new chromosome or plasmid