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Antibiotic Resistance The Miracle Revoked? Wilson “Bill” Muse 10/29/2009 The Miracle of Antibiotics Bacteria Eukaryotes Fungi Mycobacteria Gram-negative Bacteria Tobramycin Azoles Allylamines Cycloheximide Polyenes Polyoxins Nucleic acid analogs Echinocandins Streptomycin Obligately parasitic Bacteria Gram-positive Bacteria Chlamydia Penicillins Sulfonamides Cephalosporins Quinolones Rickettsia Viruses RNA viruses DNA viruses Nonnucleoside reverse-transcriptase inhibitors Protease inhibitors Fusion inhibitors Tetracycline Isoniazid Polymyxins Vancomycin Daptomycin Platensimycin Nucleoside analogs Interferon Classes of antibiotics • • • • • • • • • Aminoglycosides Tetracyclines Sulfonamides Quinolones Polypeptides B-lactams Macrolides Glycopeptides Cephalosporins Antibiotic modes of action 5 main targets • • • • • Prevent cell wall synthesis (B-lactams) Disrupt membrane function (polymyxins) Prevent protein synthesis (chloramphenicols) Prevent nucleic acid synthesis (quinolones) Disrupt metabolic pathways (sulfanilamides) Cell wall synthesis Cycloserine Vancomycin Bacitracin Penicillins Cephalosporins Monobactams Carbapenems Quinolones DNA gyrase RNA elongation Nalidixic acid Ciprofloxacin Novobiocin Actinomycin DNA-directed RNA polymerase Rifampin Streptovaricins Protein synthesis (50S inhibitors) Erythromycin (macrolides) Chloramphenicol Clindamycin Lincomycin DNA Folic acid metabolism Trimethroprim Sulfonamides THF mRNA Protein synthesis (30S inhibitors) Ribosomes DHF 50 30 50 30 50 30 Cytoplasmic membrane structure and function Polymyxins Daptomycin Lipid biosynthesis PABA Plantensimycin Cytoplasmic Cell wall membrane Tetracyclines Spectinomycin Streptomycin Gentamicin Kanamycin Amikacin Nitrofurans Protein synthesis (tRNA) Mupirocin Puromycin Antibiotics: Mechanisms of Action Inhibition of Cell Wall Synthesis -some antibiotics prevent peptidoglycan formation Examples: vancomycin, amoxicillin, ampicillin, penicillin Cross-linking of peptidoglycan transpeptidase STRUCTURE OF PENICILLIN O S C NH CH O C CH N CH3 C CH CH3 COOH Antibiotics: Mechanisms of Action Inhibition of Bacterial Protein Synthesis - some antibiotics bind to the large or small subunit of the bacterial ribosome Examples: neomycin, streptomycin, azithromycin, erythromycin, tetracycline Binding and altering ribosome structure Aminoglycosides neomycin Mechanism of Action • Once inside the cell… – Bind 30S ribosomal subunit – Blocks binding of aminoacyl-tRNA to acceptor site on mRNA-ribosome complex – Protein synthesis is inhibited = bacteriostatic effect Summary of Targets How Antibiotic Resistance Happens Overcoming the arsenal • • • • Modify antibiotic Pump it out Alter the target site Bypass the pathway Alter the drug to render ineffective O S C NH CH O C CH N CH3 C CH CH3 COOH Site of penicillinase action. Breakage of the B-lactam ring. ex: anti-streptomycin ex: anti-tetracyclins quinolines ex: anti-B-lactams ex. anti-sulfanilamides Mechanisms of antibiotic resistance •Efflux Pumps •Hydrolysis •Reduced Uptake •Sequestering •Enzymatic Modification mechanisms The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are: Drug inactivation or modification: e.g. enzymatic deactivation of Penicillin G in some penicillin-resistant bacteria through the production of ß-lactamases. Alteration of target site: e.g. alteration of PBP—the binding target site of penicillins— in MRSA and other penicillin-resistant bacteria. Alteration of metabolic pathway: e.g. some sulfonamide-resistant bacteria do not require para-aminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides. Instead, like mammalian cells, they turn to utilizing preformed folic acid. Reduced drug accumulation: by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell surface.[4] There are three known mechanisms of fluoroquinolone resistance. Some types of efflux pumps can act to decrease intracellular quinolone concentration. In gram-negative bacteria, plasmid-mediated resistance genes produce proteins that can bind to DNA gyrase, protecting it from the action of quinolones. Finally, mutations at key sites in DNA gyrase or Topoisomerase IV can decrease their binding affinity to quinolones, decreasing the drug's effectiveness.[5] Tetracyclines • Broad-spectrum activity – Includes aerobic G+ and G, atypicals [Rickettsia spp, treponema spp, chlamydia spp, and others] – Little to no effect on fungi or viruses • • • • Tetracycline Doxycycline* Minocycline Tigecycline www.3dchem.com Summary • Bacteria have evolved ways to counteract the effects of most antibiotics. • They mutate to alter target sites or recruit enzymes to degrade or pump out antibiotics • They share their tricks with other bacteria through gene transfer
