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Home , Antimicrobial, Antimicrobial resistance, Antiviral drug

Chapter 12

Topics: • Ideal - Antimicrobial Therapy - Selective • Terminology - Survey of Antimicrobial Drug • - Microbial - Drug and Interaction

An ideal antimicrobic: is the use of any chemical - soluble in body fluids, agent in the treatment of disease. - selectively toxic , - nonallergenic, A chemotherapeutic agent or drug is any - reasonable half life (maintained at a chemical agent used in medical practice. constant therapeutic concentration) An agent is usually considered to - unlikely to elicit resistance, be a chemical substance made by a - has a long shelf life, that can inhibit the growth or - reasonably priced. kill . There is no ideal antimicrobic An antimicrobic or antimicrobial agent is Selective Toxicity - that specifically target a chemical substance similar to an microbial processes, and not the human host’s. antibiotic, but may be synthetic.

Antibiotics Spectrum of antibiotics and targets

• Naturally occurring – Metabolic products of and fungi – Reduce competition for nutrients and space • Bacteria – Streptomyces, Bacillus, • – Penicillium, Cephalosporium * *

1 The for different 5 General Mechanisms of Action for antimicrobial drug targets in bacterial cells Antibiotics

- Inhibition of Wall Synthesis

- Disruption of Cell Membrane Function

- Inhibition of Synthesis

- Inhibition of Synthesis

- Anti-metabolic activity

Antibiotics weaken the , and cause the cell to lyse . Cell wall synthesis

• Bactericidal • – hinders elongation • and – binds and blocks peptidases involved in cross-linking the glycan molecules

Fig. 12.2 The consequences of exposing a growing cell to antibiotics that prevent cell wall synthesis.

Affect cell wall synthesis The mechanism of cell wall inhibition by and cephalosporins Penicillin – Figure 13.11 Penicillin G - drug of choice for streptococci, meningococci, pneumococci, spirochetes, clostridia, aerobic gram-positive rods treponemes - administered parenterally - other than by mouth - why? Penicillin V, ampicillin or other analogues may be used for oral administration Cephalosporins - similar to penicillins

2 Penicillin Penicillin continued

• Penicillin chrysogenum • Resistance – if bacteria contain st nd rd • A diverse group (1 , 2 , 3 generations) penicillinases - βββ-lactamase – Natural (penicillin G and V) • Inhibits cell wall synthesis – Semisynthetic (ampicillin, amoxicillin) • Effective against Gram+ bacteria • Structure –Beta-lactam ring – Variable side chain (R group)

Effect of β-lactamase on penicillin

Penicillins

Cephalosporin - beta lactam continued…

• Cephalosporium acremonium () • Resistant to most pencillinases • Widely administered today • Broad-spectrum – inhibits cell wall – Diverse group (natural and semisynthetic- synthesis 4th generation!) rd • Structure • 3 generation drugs used to treat – similar to penicillin except enteric bacteria, respiratory, skin, urinary and • Main ring is different • Two sites for R groups

3 Nucleic acid synthesis

• – binds and cross-links the double helix • Other quinolones – inhibits DNA unwinding (gyrase) and block replication. is an example • – Analogs of purines and pyrimidines - sometimes considered

Rifampin - blocks - can “Red Man Syndrome” cause red man syndrome - a result of accumulation of metabolic products of the antimicrobic in secretions

Examples of different antibiotics and their Mostly sites of inhibition on the prokaryotic ribosome seen with anti-viral agents

purine purine pyrimidine pyrimidine analog analog

4 Protein synthesis

• Aminoglycosides • Streptomyces and Micromonospora – Binds the 30S ribosome • Broad-spectrum – Misreads mRNA • Commonly used to treat bubonic • plague and sexually transmitted – Binds the 30S ribosome diseases – Blocks attachment of tRNA to A site • • Inhibits protein synthesis - bind 30S ribosomal subunit – Binds to the 50S ribosome – Prevents peptide bond formation

Tetracycline

• Streptomyces • Broad spectrum and low cost • Commonly used to treat sexually transmitted diseases • Side effects – gastrointestinal disruption, deposition in hard tissues • Inhibits synthesis - Binds the 30S ribosome and blocks attachment of tRNA

Chloramphenicol

• Streptomyces • Streptomyces • Broad-spectrum • Structure – ring • Only made synthetically today • Broad-spectrum • Treat typhoid fever, brain abscesses • Commonly used as prophylactic drug prior to • Side effects – aplastic anemia • Side effects - low toxicity • Inhibits protein synthesis - binds 50S ribosome subunit - prevents peptide • Inhibits protein synthesis - bind to bond formation 50S ribosome subunit- prevents translocation

5 Cell membrane Polyenes • • • Commonly used for skin infections – Interact with membrane phospholipids • Targets the membrane - loss of selective – Distorts the cell surface permeability – Leakage of proteins and nitrogen bases • Polyenes – Amp B and Nystatin • Anti-fungal - Polyenes • Amphotericin B - binds to ergosterol found – Amphotericin B and Nystatin- bind to in fungi and , but not in human sterols on cells membranes. cells - increases membrane permeability • Side effects are numerous due to toxicity of the drug

ANTIMETABOLITES Sulfonamides (sulfa drugs) Act either through competitive inhibition or erroneous incorporation – molecular • Synthetic drug mimicry • Based on • Used in combination with other Sulfonamides - block synthesis of folic synthetics such as trimethoprim acid - and as a result, nucleic acid • Commonly used to treat synthesis in AIDS patients Isoniazid - for two • Inhibits folic acid synthesis

The of sulfa drug Other types of antimicrobials

• Antiprotozoan – - most are fairly toxic - black hairy tongue – Treat Giardia and amebiasis • Antimalarial – Quinine – • Antihelminthic – mebendazole – Tapeworms, roundworms

6 Antiviral

• Limited drugs available Flagyl • Difficult to maintain selective toxicity • Effective drugs – target cycle – Entry – Nucleic acid synthesis – Assembly/release • – artificial

Antimicrobial Resistance 5 Mechanisms of Resistance 1) Alteration of Targets – usually affects • Resistance factors – R ribosomes • 5 main mechanisms of 2) Alteration of Membrane Permeability- Change resistance in the that binds the drug • New approaches 3) Development of Enzymes – βββ-lactamase

4) pumps – Memnbrane proteins many Gram negatives that pump out drug

5) Alteration of Metabolic Pathway – Development of alternate pathway

Examples of mechanisms of Demonstration of how acquired drug resistance enables resistant strains to become dominant βββ-lactamase

Membrane permeability

Efflux pumps

Alter targets

Alternate

7 Human Misuse of Limiting Resistance Antibiotics!!! 1) Constant exposure to high levels of antibiotic

2) Use of multiple antibiotics

3) Restricted use of antibiotics

New approaches

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

Drug and Host Interaction Main Types of Side Effects Associated with Antimicrobial • Toxicity to organs Treatment • Allergic reactions 1)Toxicity • Suppress/alter microflora 2) – actual drug or breakdown • Effective drugs products

3)Disruption of Normal Microflora Can Lead to !!

8 Disrupting the microflora in the intestine can Development of disease following result in superinfections broad spectrum antimicrobic therapy Pseudomembranous colitis (antibiotic associated ) - often caused by Clostridium difficile Yeast – after broad antibiotic use to treat UTI caused by E. coli

Effective drugs An example of the Kirby-Bauer Test

• Identify infectious agent • Sensitivity testing • Minimum Inhibitory Concentration (MIC) – visual call

The E-test is an alternative to the Kirby-Bauer procedure

9 Multiwell plate to calculate several MICs

Antimicrobics have helped us deal with disease, but on the other hand, improper use of antimicrobics have created new difficulties.

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