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What are chemical that affect physiology in a manner such as caffeine, alcohol, and tabacco?
What are drugs that act against disease?
- Chemotherapeutic agents, such as insulin and anticancer drugs.
- Paul Ehrlich (1854-1915), a German scientist, proposed the term chemotherapy to describe the use of chemicals that would selectively kill pathogens while having little or no effect on a patient. "Magic bullets" would bind to receptors on germs to bring about their death while ignoring host cells, which lacked the receptor molecules.
What are drugs for treating infections?
Antimicrobial agents (antimicrobials)
What bacterium is the number one cause of hospital-acquired infections in the United States?
Staphylococcus aureus, resistant to methicillin, the antimicrobial that is traditionally used to treat staphylococcal infections, and vancomycin, which was the last line of defense againt methicillin-resistant S. aureus (MRSA).
Describe Ehrlich's search for antimicrobial agents.
- Discovered one arsenic compound that killed trypanosome parasites and another that worked against the bacterial agent of syphilis.
- Ehrlich's arsenic compounds were toxic to humans.
In 1929, which British bacteriologist reported the antibacterial action of penicillin released from Penicillium mold?
- Alexander Fleming (1881-1955)
- Penicillin was not available in large enough quantities to be useful until the late 1940's.
In 1932, which German chemist discovered sulfanilamide?
- Gerhard Domagk (1895-1964)
- This was the first practical antimicrobial agent efficacious in treating a wide array of bacterial infections.
Who discovered other MO that were sources of useful antimicrobials, most notably species of soil-dwelling bacteria in the genus Streptomyces?
- Selman Waksman (1888-1973)
- Waksman coined the term antibiotics to describe antimicrobial agents that are produced naturally by an organism.
- Chemically altered antibiotics.
- More effective, longer lasting, or easier to administer than naturally occuring antibiotics.
Antimicrobials that are completely synthesized in a laboratory.
- The key to successful selecting a chemotherapeutic drug against a particular microbe.
- An effective antimicrobial agent must be more toxic to a pathogen than to the pathogen's host.
- This is possible because of differences in structure or metabolism between the pathogen and its host. More differences = easier to discover or create an effective antimicrobial agent. Because of these many differences between the structure and metabolism of pathogenic bacteria and their eukaryotic hosts, antibacterial drugs constitute the greatest number of diversity of antimicrobial agents.
- Fewer antifungal, antiprotozoan, and anthelmintic drugs are available because fungi, protozoa, and helminths (like their animal and human hosts) are eukaryotic and share many common features.
- Number of antiviral also limited, despite major differences in structure, because viruses utilize their host cells' enzymes and ribosomes to metabolize and replicate. Therefore, drugs that are effective against viral replication are likely toxic to the host as well.
What are the categories that antimicrobial drugs are grouped into according to their mechanisms of action?
- Drugs that inhibit cell wall synthesis. These drugs are selectively toxic to certain fungal or bacterial cells, which have cell walls, but not to animals, which lack cell walls).
- Drugs that inhibit protein synthesis (translation) by targeting diff between prokaryotic and eukaryotic ribosomes.
- Drugs that disrupt unique components of the cytoplasmic membrane.
- Drugs that inhibit general metabolic pathways not used by humans.
- Drugs that inhibit nucleic acid synthesis.
- Drugs that block a pathogen's recognition of or attachment to its host.
Inhibition of cell wall synthesis.
- Echinocandins (antifungal)
Inhibition of protein synthesis
Disruption of cytoplasmic membrane
- Polyenes (antifungal)
Inhibition of general metabolic pathway
Inhibition of DNA or RNA synthesis
- Nucleotide analogs
Inhibition of pathogen's attachment to, or recognition of, host
How does a cell wall protect a cell?
- It protects a cell from the effects of osmotic pressure.
- Both pathogenic bacteria and fungi have cell walls, which animals and humans lack.
What is the major structural component of a bacterial cell wall?
Its peptidoglycan layer (a huge macromolecule composed of polysaccharide chains of alternating N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) molecules that are cross-linked by short peptide chains extending between NAM subunits).
What must a cell synthesize when enlarging or dividing?
A cell must synthesize more peptidoglycan (adding new NAG and NAM subunits).
How do the most common antibacterial agents act?
By preventing the cross-linkage of NAM subunits.
What are the subunits that are cross-linked by short peptide chains?
N-acetylmuramic acid (NAM) subunits.
What are beta-lactams?
- Drugs such as penicillins and cephalosporins, which are antimicrobials whose functional portions are called beta-lactam (B-lactam) rings.
- Inhibit peptidoglycan formation by irreversibly binding to the enzymes that cross-link NAM subunits, causing bacterial cells to weaken and are less resistant to the effects of osmotic pressure.The cytoplasmic membrane bulges through the weakened portions of the cell wall as water moves into the cell, eventually causing cells to lyse.
What alterations have chemists made to natural beta-lactams?
- They have semisynthesized derivatives such as cephalothin, methicillin, and penicillin G.
- More stable in acidic enviornment of stomach.
- More readily absorbed in the intesinal tract.
- More active against more types of bacteria.
- Less susceptible to deactivation by bacterial enzymes.
What are the simplest beta-lactams?
Monobactams, which are seldom used because they are effective only against aerobic Gram-negative bacteria.
Antimicrobial - Vancomycin
- Obtained from Amycolatopsis orientalis, disrupt cell wall foremation by directly interfering with particular alanine-alanine bridges that link the NAM sub-units in many Gram-positive bacteria.
- Those bacteria that lack alanine-alanine cross bridges are naturally resistant to this drug.
- Cycloserine, a semisynthetic, works the same way.
- Result in cell lysis due to the effects of osmotic pressure.
Antimicrobial - Bacitracin
- Prevents cell wall formation and blocks the transport of NAG and NAM from the cytoplasm out to the wall.
- Result in cell lysis due to the effects of osmotic pressure.
Why do the antimicrobial drugs beta-lactams (PCN and cephalosporins), vancomycin, cycloserine, and bacitracin prevent bacteria from increasing the amount of cell wall material but have no effect on existing peptidoglycan?
Because they are only effective on bacterial cells that are growing or reproducing, dormant cells are unaffected.