Microbiology: A Systems Approach PowerPoint to accompany Microbiology: A Systems Approach Cowan/Talaro Chapter 12 Drugs, Microbes, Host- The Elements of Chemotherapy Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Chapter 12 Topics - Antimicrobial Therapy - Selective Toxicity - Survey of Antimicrobial Drug - Microbial Drug Resistance - Drug and Host Interaction

Antimicrobial Therapy Ideal drug Terminology Antibiotics

Important characteristics regarding antimicrobial drugs. Table 12.1 Characteristics of the ideal antimicrobial drug

Important terms related to chemotherapy. Table 12.2 Terminology of chemotherapy

Antibiotics Naturally occurring antimicrobials Bacteria Molds Metabolic products of bacteria and fungi Reduce competition for nutrients and space Bacteria Streptomyces, Bacillus, Molds Penicillium, Cephalosporium

Selective Toxicity Drugs that specifically target microbial processes, and not the human host cellular processes.

Selective Toxicity Mechanism of action Bacterial cell wall Nucleic acid synthesis Protein synthesis Cell membrane Folic acid synthesis

The mechanism of action for different antimicrobial drug targets in bacterial cells. Fig. 12.1 Primary sites of action of antimicrobial drugs on bacterial cells.

Cell wall synthesis Bactericidal Cycloserine – inhibits the formation of the basic peptidoglycan subunits Vancomycin – hinders peptidoglycan elongation Penicillin and cephalosporins – binds and blocks peptidases involved in cross-linking the glycan molecules

Antibiotics weaken the cell wall, and cause the cell to lyse. Fig. 12.2 The consequences of exposing a growing cell to antibiotics that prevent cell wall synthesis.

The mechanism of cell wall inhibition by penicillins and cephalosporins. Fig. 12.3 The mode of action of penicillins and cephalosporins

Nucleic acid synthesis Chloroquine – binds and cross-links the double helix Other quinolones – inhibits DNA unwinding enzymes Viruses Asidothymidine (AZT) Analogs of purines and pyrimidines

Protein synthesis Aminoglycosides Tetracyclines Chloramphenicol Binds the 30S ribosome Misreads mRNA Tetracyclines Blocks attachment of tRNA Chloramphenicol Binds to the 50S ribosome Prevents peptide bond formation

Examples of different antibiotics and their sites of inhibition on the procaryotic ribosome. Fig. 12.4 Sites of inhibition on the procaryotic ribosome and major antibiotic that act on these sites.

Cell membrane Polymyxins Anit-fungal Interact with membrane phospholipids Distorts the cell surface Leakage of proteins and nitrogen bases Anit-fungal Amphoterin B Forms complexes with sterols in the membrane Leakage Can affect human cell membranes (toxicity)

Folic acid synthesis Sulfonamides (sulfa drug) and trimethoprim Analogs Competitive inhibition Prevents the metabolism of DNA, RNA, and amino acid

Sulfonamides compete with PABA for the active site on the enzyme. Fig. 12.5 The mode of action of sulfa drug.

Survey of Antimicrobial Drugs Penicillin Cephalosporins Streptomycin Tetracyline Sulfomides Polyenes Antiviral

Important chemotherapeutic agents used to treat infectious diseases. Table 12.3 Selected survey o chemotherapeutic agents in infectious diseases.

Important chemotherapeutic agents used to treat infectious diseases. Table 12.3 Selected survey o chemotherapeutic agents in infectious diseases.

Important chemotherapeutic agents used to treat infectious diseases. Table 12.3 Selected survey o chemotherapeutic agents in infectious diseases.

Penicillin Penicillin chrysogenum A diverse group (1st, 2nd , 3rd generations) Natural (penicillin G and V) Semisynthetic (ampicillin) Structure Thiazolidine ring Beta-lactam ring Variable side chain (R group)

Penicillin continued Resistance – if bacteria contain penicillinases Inhibits cell wall synthesis Treat streptococci, meningococci, and spirochete infections

The R group is responsible for the activity of the drug, and cleavage of the beta-lactam ring will render the drug inactive. Fig. 12.6 Chemical structure of penicillins

Cephalosporin Cephalosporium acremonium (mold) Widely administered today Diverse group (natural and semisynthetic) Structure similar to penicillin except Main ring is different Two sites for R groups

Cephalosporin continued Resistant to most pencillinases Broad-spectrum – inhibits cell wall synthesis 3rd generation drugs used to treat enteric bacteria, respiratory, skin, urinary and nervous system infections

The different R groups allow for versatility and improved effectiveness. Fig. 12.7 The structure of cephalosporins

Aminoglycosides Streptomyces and Micromonospora Structure Amino sugars and an aminocyclitol ring Broad-spectrum Commonly used to treat bubonic plague and sexually transmitted diseases Inhibits protein synthesis

The amino sugars and six-carbon ring (aminocyclitol) are characteristics associated with streptomycin. Fig. 12.8 The structure of streptomycin

Streptomyces synthesizes many different antibiotics such as aminoglycosides, tetracycline, chloramphenicol, and erythromycin. Fig. 12.9 A colony of Streptomyces

Tetracycline Streptomyces Structure – Broad spectrum and low cost Diverse complex series of rings Broad spectrum and low cost Commonly used to treat sexually transmitted diseases Side effects – gastrointestinal disruption Inhibits proteins synthesis

Chloramphenicol Streptomyces Structure - nitrobenzene structure Broad-spectrum Only made synthetically today Treat typhoid fever, brain abscesses Side effects – aplastic anemia Inhibits protein synthesis

Erythromycin Streptomyces Structure – macrolide ring Broad-spectrum Commonly used as prophylactic drug prior to surgery Side effects - low toxicity Inhibits protein synthesis

Comparison of three broad-spectrum antibiotics tetracycline, chloramphenicol, and erythromycin. Fig. 12.10 Structures of three broad-spectrum antibiotics

Sulfonamides (sulfa drugs) Synthetic drug Based on sulfanilamides Used in combination with other synthetics such as trimethoprim Commonly used to treat pneumonia in AIDS patients Inhibits folic acid synthesis

Attachment of different R groups to the main structural nucleus enables versatility of sulfonamides. Fig. 12.11 The structures of some sulfonamides

Polyenes Antifungal Structure – large complex steroidal structure Some toxicity to humans Commonly used for skin infections Targets the membrane - lost of selective permeability

Comparison of different antifungal drug structures, which include polyenes, azoles, and flucytosine. Fig. 12.12 Some antifungal drug structures

Other types of antimicrobials Antiprotozoan – metronidazole Treat giardia Antimalarial – Quinine malaria Antihelminthic – mebendazole Tapeworms, roundworms

Antiviral Limited drugs available Difficult to maintain selective toxicity Effective drugs – target viral replication cycle Entry Nucleic acid synthesis Assembly/release Interferon – artificial antiviral drug

Antiviral drug structures and their mode of action. Table 12.5 Actions of selected antiviral drugs.

Antiviral drug structures and their mode of action. Table 12.5 Actions of selected antiviral drugs.

Antiviral drug structures and their mode of action. Table 12.5 Actions of selected antiviral drugs.

Antimicrobial Resistance Resistance factors New enzymes Permeability Alter receptors Change metabolic patterns Natural selection New approaches

Intermicrobial transfer of plasmids containing resistance genes (R factors) occurs by conjugation, transformation,and transduction. Fig. 12.13 Spread of resistance factors

Different mechanisms that are commonly associated with drug resistance. Fig. 12.14 Examples of mechanisms of acquired drug resistance

Demonstration of how natural selection enables resistant strains to become dominant. Fig. 12.15 The events in natural selection for drug resistance

New approaches Increase drug resistance requires new approaches for developing effective antimicrobials Prevent iron –scavenging capabilities Inhibit genetic controls (riboswitches) Probiotics and prebiotics

Drug and Host Interaction Toxicity to organs Allergic reactions Suppress/alter microflora Effective drugs

Tetracycline treatments can cause teeth discoloration. Fig. 12.16 Drug-induced side effect.

Disrupting the microflora in the intestine can result in superinfections. Fig. 12.17 The role of antimicrobials in disrupting microbial Flora

Summary of antimicrobial drugs, the primary tissues affected, and the damage produced. Table 12.6 Major adverse toxic reactions to common drug groups.

Effective drugs Identify infectious agent Sensitivity testing Minimum Inhibitory Concentration (MIC)

Sensitivity test such as the Kirby-Bauer Test can be used to determine the effectiveness of a drug by measuring the zone of inhibition. Table 12.7 Results of a sample kirby-bauer test

An example of the Kirby-Bauer Test. Fig. 12.18 Technique for preparation and interpretation of disc diffusion test.

The E-test is an alternative to the Kirby-Bauer procedure. Fig. 12.19 Alternative to the Kirby-Bauer

The dilution test is an effective method of determining the MIC. Fig. 12.20 Tube dilution test for determining the MIC

The lower the MIC, the more effective the drug is toward combating the bacterium. Table 12.8 Comparative MICs