Chapter 10: Controlling Microbial Growth in the Body: Antimicrobial DrugsWhy is this important?• One hundred years ago in the U.S., one out of three children was expected to die of an infectious disease before the age of 5• The introduction of modern drugs to control infections in the 1930s added significantly to the life span and health of humans– Scientists estimate that penicillin alone has saved 200 million lives• Need to understand the mode of action of a drug in order to understand if a particular antibiotic will be effective against a given pathogen• Antibiotic resistance is becoming more and more of a problem in our society– Longer and more expensive hospital stays– More likely to die– The more antibiotic resistance the more antibiotics we will see The History of Antimicrobial Agents• At the beginning of the 20th century, Paul Ehrlich proposed the term chemotherapy to describe the use of chemicals that would selectively kill pathogens while having little to no effect on a patient– Discovered Salvarsan (arsenic compound-not entirely safe)– Selectively killed pathogens with little effect on humans • In 1928 Alexander Fleming reported the antibacterial action of penicillin (derived from Penicillium)– First true antibiotic • Sulfanilamide was the first practical antimicrobial agent effective in treating awide array of bacterial infections (1932)• Selman Waksman discovered that other microbes also produce antibiotics; Streptomyces– Coined the term antibiotic – antimicrobial agent that is produced naturally by an organism• Semisynthetic antimicrobials• Synthetic drugs• A lot of bacteria is used to make antibiotics as wellMechanisms of Antimicrobial Action• Key is selective toxicity – an effective antimicrobial agent must be more toxic to a pathogen than to the pathogen’s host– Don’t give medicine that will kill the patient in the process – Possible because of differences in structure or metabolism between the pathogen and its host• Antibacterial drugs constitute largest number and diversity of antimicrobial agents• Fewer antifungal, antiprotozoan, and anthelmintic drugs because these organisms are eukaryotic in nature and share many common features with humans and animals– Not nearly as many differences • The number of effective antiviral drugs is also limited– Because they are obligate intercellular parasites so they are making use of host cell metabolism– So many times you kill the host in the process Mechanisms of Antimicrobial Action **VIDEO**• Easier to develop antibacterial drugs • Few differences between fungi and animal cells• Anti bacterial drugs mode of actions - ways they work• Block formation of bacterial cell walls during replication • Penicillin breaks cell wall cross links• Causes cell to lyse• Drugs bind to phospholipids and pokes holes• In terms of phospholipids they are the same in pro and eukaryotes so it isn't selective• Use externally because cells are already dead on skin• Inhibiting protein synthesis• In order to make protein ribosomes are involved • Ribosome size are different in prokaryotes and eukaryotes (70S and 80S cells)• There can be some effects because there are mitochondria (70S) in cells---especially in bone marrow• Prevention of peptide bonds• Cause a change in the shape of the 30S subunit – insertion of incorrect amino acids• Inhibition of metabolic pathways• Block DNA gyrase • DNA gyrase uncoils the DNA • Block transcription, replication, and translationInhibition of Cell Wall Synthesis• Cell wall protects a cell from the effects of osmotic pressure• Bacteria and fungi have cell walls; humans and animals lack• Drugs that act against bacterial cell walls– Most common antibacterial agents act by preventing the cross-linkage of NAM subunits– Another drug blocks transport of NAG and NAM from the cytoplasm out to the wall– Common features– Prevent bacteria from increasing the amount of cell wall, but have no effect on existing peptidoglycan layer– Effective only for growing cells; dormant cells are unaffected– Drugs effective against acid-fast positive organisms disrupt the formation of the arabinogalactan-mycolic acid layer• Inhibition of Synthesis of Fungal Walls– Fungal walls composed of various polysaccharides containing a sugar, 1,3-D-glucan, that is not found in mammalian cells– Drugs inhibit the enzyme that synthesizes glucan– Selective toxicityInhibition of Protein Synthesis• Recall that prokaryotic ribosomes are 70S (30S and 50S subunits) while eukaryotic ribosomes are 80S (40S and 60S subunits)• Antimicrobial agents selectively target bacterial protein translation without significantly affecting eukaryotes– Mitochondria of animals and humans contain 70S ribosomes, so such drugs can be harmful to very active cells of the liver and bone marrow of humans and animalsDisruption of Cytoplasmic Membranes• Some drugs disrupt the cytoplasmic membrane of a targeted cell, often by forming a channel through the membrane, damaging its integrity• Disruption of fungal membranes– Ergosterol is a lipid constituent in fungal membranes and is a target ofseveral drugs– Humans somewhat susceptible – Most bacteria lack sterols; not susceptible• Disruption of bacterial membranes– Polymyxin effective against Gram-negatives; toxic to human kidneys– Reserved for use against external pathogens– Certain drugs transport across the cytoplasmic membrane• Disruption of cytoplasmic membrane of parasites– Certain drugs change the permeability of cytoplasmic membranesInhibition of Metabolic Pathways• Metabolism is the sum of all chemical reactions that take place within an organism– Most living things share certain metabolic reactions– Some chemical reactions are unique to certain organisms• When differences exist between metabolic processes of pathogen and host, antimetabolic agents can be effective– One agent interferes with electron transport in protozoa and fungi– Certain heavy metals inactivate enzymes– Agents that disrupt tubulin polymerization and glucose uptake by many protozoa and parasitic worms– Drugs that block the activation of viruses– Metabolic antagonists (sulfanilamide)• Antiviral agents can target unique aspects of viral metabolism– Viruses must penetrate cytoplasmic membrane and be uncoated• Some are uncoated as a result of the acidic environment within phagolysosomes•