Antimicrobial Drugs

Fading Miracle?

Keajaiban yang kabur? Ehrlichs Magic Bullets Fleming and Penicillin

Chemotherapy The use of drugs to treat a disease

Selective toxicity: A drug that kills harmful microbes without damaging the host

Antibiotic/Antimicrobial

Antibiotic: Chemical produced by a microorganism that kills or inhibits the growth of another microorganism

Antimicrobial agent: Chemical that kills or inhibits the growth of microorganisms

Microbial Sources of Antibiotics Antibiotic Spectrum of Activity No antibiotic is effective against all microbes

Mechanisms of Antimicrobial Action

Bacteria have their own enzymes for

Cell wall formation Protein synthesis DNA replication RNA synthesis Synthesis of essential metabolites

Mechanisms of Antimicrobial Action Viruses use host enzymes inside host cells Fungi and protozoa have own eukaryotic enzymes

The more similar the pathogen and host enzymes, the more side effects the antimicrobials will have Modes of Antimicrobial Action Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis Penicillin (over 50 compounds)

Share 4-

Natural penicillins

Narrow range of action

Penicillins Fig 20.6

Susceptible to

Prokaryotic Cell Walls

Semisynthetic Penicillins Penicilinase-resistant penicillins

Carbapenems: very broad spectrum Monobactam: Gram negative

Extended-spectrum penicillins Penicillins + -lactamase inhibitors Other Inhibitors of Cell Wall Synthesis Cephalosporins

2nd, 3rd, and 4th generations more effective against gram-negatives

Other Inhibitors of Cell Wall Synthesis Polypeptide antibiotics Bacitracin

Topical application

Against gram-positives

Vancomycin Glycopeptide Important "last line" against antibiotic resistant S. aureus

Other Inhibitors of Cell Wall Synthesis Antibiotics effective against Mycobacteria: interfere with mycolic acid synthesis or incorporation

Isoniazid (INH) Ethambutol

Inhibitors of Protein Synthesis Broad spectrum, toxicity problems Examples

Chloramphenicol (bone marrow/sumsum tlg) Aminoglycosides: Streptomycin, neomycin, gentamycin (hearing, kidneys) Tetracyclines (Rickettsias & Chlamydia; GI tract) Macrolides: Erythromycin (gram +, used in children)

Inhibitors of Nucleic Acid Synthesis Rifamycin

Inhibits RNA synthesis

Antituberculosis

Quinolones and fluoroquinolones Ciprofloxacin Inhibits DNA gyrase Urinary tract infections

Injury to the Plasma Membrane Polymyxin B (Gram negatives) Combined with bacitracin and neomycin (broad spectrum) in over-the-counter preparation

Competitive Inhibitors Sulfonamides (Sulfa drugs)

Inhibit folic acid synthesis Broad spectrum

Antifungal Drugs Fungi are eukaryotes Have unique sterols in their cell walls Pathogenic fungi are often outside the body Antiviral Drugs Viruses are composed of nucleic acid, protein capsid, and host membrane containing virus proteins

Viruses live inside host cells and use many host enzymes Some viruses have unique enzymes for DNA/RNA synthesis or protein cutting in virus assembly Antiviral Drugs Nucleoside and Nucleotide Analogs Analogs Block DNA Synthesis Antiviral Drugs Enzyme Inhibitors Inhibit assembly

Indinavir (HIV)

Inhibit attachment Zanamivir (Influenza)

Inhibit uncoating Amantadine (Influenza)

Antiviral Drugs Enzyme Inhibitors Interferons prevent spread of viruses to new cells (Viral hepatitis) Natural products of the immune system in viral infections Antiprotozoan Drugs Protozoa are eukaryotic cells Many drugs are experimental and their mode of action is unknown

Measuring Antimicrobial Sensitivity E Test MIC: Minimal inhibitory concentration

Measuring Antimicrobial Sensitivity: Disk Diffusion Antibiotic Resistance Antimicrobial Resistance

Relative or complete lack of effect of antimicrobial against a previously susceptible microbe

Increase in MIC Mechanisms of Antibiotic Resistance

Enzymatic destruction of drug Prevention of penetration of drug Alteration of drug's target site Rapid ejection of the drug

Antibiotic Selection for Resistant Bacteria

What Factors Promote Antimicrobial Resistance?

Exposure to sub-optimal levels of antimicrobial

Exposure to microbes carrying resistance genes

Inappropriate Antimicrobial Use

Prescription not taken correctly

Antibiotics for viral infections

Antibiotics sold without medical supervision

Spread of resistant microbes in hospitals due to lack of hygiene

Inappropriate Antimicrobial Use Lack of quality control in manufacture or outdated antimicrobial Inadequate surveillance or defective susceptibility assays Poverty or war Use of antibiotics in foods

Antibiotics in Foods Antibiotics are used in animal feeds and sprayed on plants to prevent infection and promote growth Multi drug-resistant Salmonella typhi has been found in 4 states in 18 people who ate beef fed antibiotics

Consequences of Antimicrobial Resistance

Infections resistant to available antibiotics

Increased cost of treatment

Multi-Drug Resistant TB Vancomycin Resistant Enterococci Vancomycin Use USA

Proposals to Combat Antimicrobial Resistance Speed development of new antibiotics Track resistance data nationwide Restrict antimicrobial use Direct observed dosing (TB)

Proposals to Combat Antimicrobial Resistance

Use more narrow spectrum antibiotics The Future of Chemotherapeutic Agents Antimicrobial peptides

Broad spectrum antibiotics from plants and animals

Squalamine (sharks)

Protegrin (pigs) Magainin (frogs)

The Future of Chemotherapeutic Agents Antisense agents Complementary DNA or peptide nucleic acids that binds to a pathogen's virulence gene(s) and prevents transcription