antimicrobial drugs fading miracle? ehrlich’s magic bullets

Antimicrobial Drugs

Fading Miracle?

Ehrlich’s 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

• Penicillin (over 50 compounds)– Share 4-sided ring ( lactam ring)

• Natural penicillins• Narrow range of action• Susceptible to penicillinase ( lactamase)

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis

Prokaryotic Cell Walls

PenicillinsFig 20.6

Figure 20.6

Penicillinase ( Lactamase)

Figure 20.8

• Penicilinase-resistant penicillins• Carbapenems: very broad spectrum• Monobactam: Gram negative

• Extended-spectrum penicillins

• Penicillins + -lactamase inhibitors

Semisynthetic Penicillins

• Cephalosporins– 2nd, 3rd, and 4th

generations more effective against gram-negatives

Other Inhibitors of Cell Wall Synthesis

Figure 20.9

• Polypeptide antibiotics– Bacitracin

• Topical application• Against gram-positives

– Vancomycin• Glycopeptide• Important "last line" against antibiotic resistant S.

aureus

Other Inhibitors of Cell Wall Synthesis

Other Inhibitors of Cell Wall Synthesis

• Antibiotics effective against Mycobacteria: interfere with mycolic acid synthesis or incorporation– Isoniazid (INH)– Ethambutol

• Broad spectrum, toxicity problems

• Examples– Chloramphenicol (bone marrow)– Aminoglycosides: Streptomycin, neomycin, gentamycin

(hearing, kidneys)– Tetracyclines (Rickettsias & Chlamydia; GI tract)– Macrolides: Erythromycin (gram +, used in children)

Inhibitors of Protein Synthesis

• Polymyxin B (Gram negatives)– Topical– Combined with bacitracin and neomycin (broad

spectrum) in over-the-counter preparation

Injury to the Plasma Membrane

• Rifamycin– Inhibits RNA synthesis– Antituberculosis

• Quinolones and fluoroquinolones– Ciprofloxacin– Inhibits DNA gyrase– Urinary tract infections

Inhibitors of Nucleic Acid Synthesis

– Sulfonamides (Sulfa drugs)• Inhibit folic acid synthesis• Broad spectrum

Competitive Inhibitors

Figure 5.7

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

Figure 20.16a

Antiviral DrugsNucleoside and Nucleotide Analogs

Figure 20.16a

Figure 20.16b, c

Analogs Block DNA Synthesis

• Inhibit assembly– Indinavir (HIV)

• Inhibit attachment– Zanamivir (Influenza)

• Inhibit uncoating– Amantadine (Influenza)

Antiviral DrugsEnzyme Inhibitors

• Interferons prevent spread of viruses to new cells (Viral hepatitis)

• Natural products of the immune system in viral infections

Antiviral DrugsEnzyme Inhibitors

Antiprotozoan Drugs

• Protozoa are eukaryotic cells

• Many drugs are experimental and their mode of action is unknown

Antihelminthic Drugs

• Helminths are macroscopic multicellular eukaryotic organisms: tapeworms, roundworms, pinworms, hookworms

• Prevent ATP generation (Tapeworms)

• Alters membrane permeability (Flatworms)

• Neuromuscular block (Intestinal roundworms)

• Inhibits nutrient absorption (Intestinal roundworms)

• Paralyzes worm (Intestinal roundworms)

Antihelminthic Drugs

Measuring Antimicrobial Sensitivity

• E Test• MIC: Minimal

inhibitory concentration

Measuring Antimicrobial Sensitivity: Disk Diffusion

Figure 20.20

Antibiotic Resistance

Antimicrobial Resistance

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

• Increase in MIC

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

Mechanisms of Antibiotic Resistance

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

MRSA “mer-sah”

• Methicillin-Resistant Staphylococcus aureus

• Most frequent nosocomial (hospital-acquired) pathogen

• Usually resistant to several other antibiotics

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

• Use antimicrobial cocktails

• 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

The Future of Chemotherapeutic Agents