Antimicrobial Drugs

Enny Suswati, dr. MKes.

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-sided ring (b lactam ring)

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

Prokaryotic Cell Walls

Penicillins
Fig 20.6

Figure 20.6

Penicillinase (b Lactamase)

Figure 20.8

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

Extended-spectrum penicillins Penicillins + b-lactamase inhibitors

Other Inhibitors of Cell Wall Synthesis

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

Figure 20.9

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

Injury to the Plasma Membrane

Polymyxin B (Gram negatives)
Topical Combined with bacitracin and neomycin (broad spectrum) in over-the-counter preparation

Inhibitors of Nucleic Acid Synthesis

Rifamycin
Inhibits RNA synthesis Antituberculosis

Quinolones and fluoroquinolones

Ciprofloxacin Inhibits DNA gyrase Urinary tract infections

Competitive Inhibitors
Sulfonamides (Sulfa drugs)
Inhibit folic acid synthesis Broad spectrum

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 Drugs
Nucleoside and Nucleotide Analogs

Figure 20.16a

Analogs Block DNA Synthesis

Figure 20.16b, c

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

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

Antihelminthic Drugs
Prevent ATP generation (Tapeworms) Alters membrane permeability (Flatworms) Neuromuscular block (Intestinal roundworms) Inhibits nutrient absorption (Intestinal roundworms) Paralyzes worm (Intestinal roundworms)

Measuring Antimicrobial Sensitivity

E Test MIC: Minimal inhibitory concentration

Measuring Antimicrobial Sensitivity: Disk Diffusion

Antibiotic Resistance

Figure 20.20

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

MRSA mer-sah
Methicillin-Resistant Staphylococcus aureus Most frequent nosocomial (hospitalacquired) 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 rationale antimicrobial

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