Broetz-Oesterhelt

Discovered 1928 by alexander fleming, purified by howard florey & ernst chain in 1942

Penicillium notatum

Any compound produced by one microbial species that could kill or inhibit the growth of other microbes

Also used for synthetic chemotherapeutic agents, such as sulfonamides, that are clinically useful but chemically synthesized

Reserved for agents that kill bacteria ≠ antifungals ≠ antiprotozoan ≠ antivirals

• must affect the target organism (e.g. peptidogylcen, bacterial ribosomes,..)

• Mus not affect humans

• Must reach target inside human body

• Many have side effects at high concentrations

Effective against many species

Effective against few or single species

Most discovered as natural products, often modified by artificial means (semi synthesis or total synthesis)

Antibiotics kill target organisms e.g. inhibitors of cell wall synthesis

Antibiotics preven growth of organisms e.g. antiniotics that stall ribosome movement

-> cannot kill an organism, Immune system removes arrested bacteria (the patient needs to be immune-competent)

= minimal inhibitory concentration

• the lowest concentration of antibacterial drug that prevents growth - varies for different bacterial species & drugs

• Lowest concentration with visible growth: broth may still contain living but non growing organisms

-> doesn not indicate if an antibiotic is bacteriostatic or bactericidal

= minimal bactericidal concentration

• plate & count colonies

• 99,9% reduction of viable bacteria

• MBC always higher than MIC

• cell wall

• DNA synthesis

• RNA synthesis

• Protein synthesis

• Metabolism

• Cal membrane

The beta-lactam ring chemically resembles the D-Ala-D-Ala piece of peptidogylcan

-> this molecular mimikry allows the drug to bind covalently to the active site serines of transpeptidases (which is why the proteins are called penicillin-binding proteins) -> preventing crosslinking of peptidoglycan

E.g. Penicillins, Cephalospoines

Binds ends of peptidoglycen peptides at the outside of the membrane

-> prevents action of transglycosylases & transpeptidases

Inhibition of the D-Ala-D-Ala dipeptide precursor

-> inhibits formation of cytoplasmatic peptidoglycan precursor in the cytoplasm

Forms a complex with bactoprenol-PP

-> inhibits recycling of lipid carrier

Bacitracin sequesters the membran carrier in its C55-PP state & inhibits its recycling

Block bacterila DNA gyrase (= topoisomerase II) & topoisomerase IV, prevent DNA replication & DNA decatenation

-> ezymes can introuce brekas but quinolones prevent enzymes from resealing the breaks

E.g. ciprofloxacin

Analogs of para aminobenzoic acid, a precuros of folic acid. Folic acid is needed for tetrahydrofolic acid synthesis & the latter for DNA synthesis

Antibiotics that inhibit transcription are bactericidal & most active againt growing bacteria

binds to RNA polymerase

-> prevents elongation step of transcription

Rifampin is the natural product, Rifamycin (derivative) is the commercial drug

Affect 30S subunit of bacterila ribosome

-> cause the translational misreading of mRNA: worng tRNAs are allowed to bind

Bactericidal

Affect the 30S subunit of bacterial ribosomes

-> block the binding of charged tRNAs to the A site of the ribosome: no tRNAs bind -> stop protein synthesis

Translation stalling agent -> bacteriostatic

Affect the 50S subunit of bacterial ribosomes

-> inhibit translocation

E.g. erythromycin

Affect 50S subunit of bacterial ribosomes

-> inhibit translocation

E.g. lincomycin

Affects the 50S subunit of bacterial ribosomes

-> inhibits peptidyl transferase activity

Affect 50S subunit of bacterial ribosomes

-> prevent formation of the 70S ribosome initiation complex

• viruses misuse eukrayotic cellular machineries for their own purpose -> difficult targets

• As typical antiviral targets function the few preoteins encoded in the viral genomes

• Alternative treatment concept: Help the eukaryotic cells to protect themselves against viral entry

• Antiviral therapy has always a narrow spectrum

• Antibiotics do not act against viruses

• Most antiviral agents work by inhibiting viral DNA synthesis

-> these drugs resemble normal DNA nucleosides but lack a 3’ OH and so cause chain termination

Anti influenza therapy

-> block neuraminidase of influenza A & B, both prevent release of mature viruses

Anti - influenza therapy

-> inhibits influenza A uncoating, prevents entry of viral RNA into host nucleus

Not much used due to neurological side effects

Anti herpes therapy

• nucleosid analogon

• Thymidine kinase og HSV phosphorylates the compound selectively to mono-phosphate

• Eukaryotic kinase phosphorylates to triphosphate

• Instertion into DNA

• Chain termination due to lack of 3’-OH

The reverse trnascriptase enzyme is unique to retroviruses: translates RNA to DNA

(Nucleoside RT inhibitors & non-nucleoside RT inhibitors)

HIV makes long, nunfunctional polypeptide chains that are cleaved by HIV protease to make mature proteins

CCR5 inhibitors block HIV from binding to host cell receptor

Fusion inhibitors prevent HIV membrane fusing with T-cell membrane

Fungal infections are much more difficult to treat than bacterial infections: fungi are eukaryotes and selective toxicity issues arise, fungi have an efficient drug detoxification system that modifies & inactivates many drugs

Two groups:

• superficila mycoses: treated topically

• Deep mycoses: treated systemicall

Inhibit the ergosterole synthesis

E.g. clotrimazole, itraconazole, fluconazole

Form pores in fungal cell membranes

Preduced by Streptomyces species

E.g. amphotericin B, nystatin

Inhibit synthesis of glucan in the fungal cell wall

Disrupts the mitotic spindle

Produced by Penicillium species

… use apropriate treatments

• antibiotics dont work on all bacteria

• Many bacteria are now drug resistant

• Antibacterials do not work on viruses

… anticipate pathogen-specific sequelae (disease complications)

… track spread of disease expansion (epidemiology)

• allows faster treatment of others infected

• Allows identification of cause & infection

Removes nonpathogens (normal microbiota), allows growth of pathogen: more cells makes testing easier, ability to grow on specific medium helps identification

Exploits pathogenss unique biochemical properties

Strains grow but differ in indicator color, based on ability to utilize material on plate

Organism is subject to the analytical profile index (API strip technology)

• a battery of biochmeical tests in 20 seperate chambers

• A 24-hour incubation indicates positive or negative reactions depending on the color

• Nowadays most clinical laboratories have automated procedures

= polymerase chain reaction

• amplifies samll fragments of DNA

• Allows detection of tiny numbers of bacteria

• Size of fragment can indicate species, strain

• Multiplex PCR uses multiple sets of primers

• Restriction analysis can further indicate strain: single nucleotide differenses affect ability to be cut by restriction enzymes

= enzyme-linked immunisorbent asssay)

• can detect antigens or antibodies present in nanogram and picogram qunatities

• Antigen from virus is attached to wells

• Patient serum is added: antibody binds to viral antigen

• Secondary antibodies have anzyme attached: bind to Fc portion of serum antibodies

• Enzyme reaction causes color change: indicates presence of antivirus antibodies in serum

= Point-of-care

• designed to be used directly at the site of patient care

• Commercial POC tests are widely available for the diagnosis of bacterial & virla infections & for parasitic diseases including malaria

• Sensitivity may be compromised

Advantages:

• culturing not required

• Immediately initiate specific antibiotic therapy

Disadvantages

• No data on pathogen antibiotic sensitivity

• Double or multiple infections are mire likely to be overlooked

• False positive and false negative can vary

Always present at a low frequency in a population

High frequency over short time

An epidemic that occurs over a wide geographic area