Drugs, Microbes, Host – The Elements of Chemotherapy

Antibiotics - Still Miracle Drugs

Paul Ehrlich’s Magic Bullets

Salvarsan No. 606

Fleming and Penicillin

Antibiotics

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

Antibiotics• Naturally occurring antimicrobials

– Metabolic products of bacteria and fungi– Reduce competition for nutrients and

space• Bacteria that produce them:

– Streptomyces, Bacillus,• Molds

– Penicillium, Cephalosporium

Selective Toxicity

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

Selective ToxicityMechanisms and sites

• Mechanism of action

–Bacterial cell wall

–Nucleic acid synthesis

–Protein synthesis

–Cell membrane

–Folic acid synthesis

Cell wall synthesis

Bactericidal– Penicillin and cephalosporins – binds

and blocks peptidases involved in cross-linking the glycan molecules

– Vancomycin – hinders peptidoglycan elongation

– Cycloserine – inhibits the formation of the basic peptidoglycan subunits

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

The mechanism of action of penicillins and cephalosporins.

Penicillin• Penicillin chrysogenum

• A diverse group (1st, 2nd , 3rd generations)

– Natural (penicillin G and V)

– Semisynthetic (Ampicillin, Carbenicillin)

• Structure

– Thiazolidine ring

– Beta-lactam ring

– Variable side chain (R group)

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

Chemical structure of penicillins

Penicillinase ( Lactamase)

Cephalosporin• Cephalosporium acremonium (mold)• Widely administered today

– Diverse group (natural and semisynthetic)– 1st, 2nd, and 3rd generations

• Structure – similar to penicillin except

• Main ring is different• Two sites for R groups

The different R groups allow for versatility and improved effectiveness.

The structure of cephalosporins

Inhibition of Protein synthesis• Aminoglycosides

– Bind to the 30S ribosome– Causes Misreading of mRNA

• Tetracyclines– Block attachment of tRNA

• Chloramphenicol– Binds to the 50S ribosome– Prevents peptide bond

formation

• Broad spectrum, toxicity problems

• Examples– Aminoglycosides: Streptomycin,

neomycin, gentamycin

– Tetracyclines

– Macrolides: Erythromycin

– Chloramphenicol

Inhibitors of Protein Synthesis

Aminoglycosides• From Streptomyces

• Inhibit protein synthesis

Streptomyces synthesizes many different antibiotics such as aminoglycosides, tetracycline, chloramphenicol, and erythromycin.

Tetracycline

• Inhibits proteins synthesis• Broad spectrum and low cost• Commonly used to treat sexually

transmitted diseases• Minor side effect – gastrointestinal

disruption

Erythromycin

• Inhibits protein synthesis

• Broad-spectrum

• Commonly used as prophylactic drug prior to surgery

• Side effects - low toxicity

Chloramphenicol

• Inhibits protein synthesis

• Broad-spectrum

• Treat typhoid fever, brain abscesses

• Rarely used now due to side effects – aplastic anemia

Aminoglycoside

Sites of inhibition on the procaryotic ribosome

• 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

Folic acid synthesis

Sulfonamides (sulfa drug) and trimethoprim

– Analogs

– Competitive inhibition of enzymes

– Prevents the metabolism of DNA, RNA, and amino acid

Sulfonamides compete with PABA for the active site on the enzyme.

The sulfonamide Sulfamethoxazole is commonly used in combination with trimethoprim

Antiviral

• Increasing types of drugs becoming available • However, it is difficult to maintain selective

toxicity• Effective drugs – target viral replication cycle

– Entry– Nucleic acid synthesis– Assembly/release

• Interferon – genetically engineered antiviral protein from a human gene

Antiviral drug structures and their unique modes of action.

Antiviral drug structures and their unique modes of action.

Antiviral drug structures and their uniquemodes of action.

Other types of antimicrobials

• Antifungal – ketoconizole

• Antiprotozoan – metronidazole

– Treat giardia

• Antimalarial – Quinine

– malaria

• Antihelminthic – mebendazole

– Tapeworms, roundworms

• Enzymatic destruction of drug

• Prevention of penetration of drug

• Alteration of drug's target site

• Rapid ejection of the drug

Mechanisms of Antibiotic Resistance

Antimicrobial Resistance

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

Figure 20.20

Antibiotic Resistance

Figure 20.20

Antibiotic ResistanceIntermicrobial transfer of plasmids containing resistance genes (R factors) occurs by conjugation, transformation,and transduction

What Factors Promote Antimicrobial Resistance?

• Exposure to sub-optimal levels of antimicrobial

• Inappropriate use• 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

• Inadequate surveillance or defective susceptibility assays

• Poverty or war• Use of antibiotics in foods• Lack of quality control in manufacture or

outdated antimicrobial

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

Antibiotic Drug and Host Interaction

• Toxicity to organs

• Allergic reactions

• Suppress/alter microflora

• Effective drugs

Tetracycline treatments can cause teeth discoloration.

Disrupting the normal flora in the intestine can result in superinfections.

Finding an effective drug for trreatment

• Identify infectious agent

• Perform sensitivity testing

• Often the Minimum Inhibitory Concentration (MIC) is determined

The Kirby-Bauer Test.

Sensitivity test such as the Kirby-Bauer Test can be used to determine the effectiveness of a drug by measuring the zone of inhibition.

Consequences of Antimicrobial Resistance

• Infections resistant to available antibiotics

• Increased cost of treatment

Multi-Drug Resistant TB

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