Slide 1Why is this important?The History of Antimicrobial AgentsThe History of Antimicrobial AgentsMechanisms of Antimicrobial ActionMechanisms of Antimicrobial ActionMechanisms of Antimicrobial ActionInhibition of Cell Wall SynthesisInhibition of Synthesis of Bacterial WallsInhibition of Cell Wall SynthesisInhibition of Synthesis of Fungal WallsInhibition of Protein SynthesisInhibition of Protein SynthesisDisruption of Cytoplasmic MembranesDisruption of Cytoplasmic MembranesInhibition of Metabolic PathwaysInhibition of Metabolic PathwaysInhibition of Metabolic PathwaysInhibition of Nucleic Acid SynthesisInhibition of Nucleic Acid SynthesisPrevention of Virus AttachmentClinical Considerations in Prescribing Antimicrobial DrugsSpectrum of ActionEfficacyRoutes of AdministrationRoutes of AdministrationSafety and Side EffectsThe Development of Resistance in PopulationsThe Development of Resistance in PopulationsMechanisms of ResistanceMechanisms of ResistanceMultiple Resistance and Cross ResistanceRetarding ResistanceM I C R O B I O L O G YWITH DISEASES BY BODY SYSTEM SECOND EDITIONChapter 10Controlling Microbial Growth in the Body: Antimicrobial Drugs THIRDWhy is this important?•Antibiotics have saved enormous numbers of lives since they were introduced in 1940–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 dieThe 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)•Alexander Fleming reported the antibacterial action of penicillin (derived from Penicillium)•Sulfanilamide was the first practical antimicrobial agent effective in treating a wide 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•Semisynthetics•SyntheticsThe History of Antimicrobial AgentsMechanisms of Antimicrobial Action•Key is selective toxicity•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•The number of effective antiviral drugs is also limitedMechanisms of Antimicrobial ActionMechanisms of Antimicrobial ActionModes of ActionInhibition of Cell Wall Synthesis•Cell wall protects a cell from the effects of osmotic pressure•Bacteria and fungi have cell walls; humans and animals lackInhibition of Synthesis of Bacterial Walls•Most common antibacterial agents act by preventing the cross-linkage of NAM subunits–Beta-lactams are most prominent in this group–Other antimicrobials directly interfere with particular alanine-alanine bridges that link the NAM subunits in many Gram-positive bacteria•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•Isoniazid and ethambutol disrupt formation of arabinogalactan-mycolic acid in mycobacterial speciesInhibition of Cell Wall Synthesis•Semisynthetic derivatives of beta-lactams –More stable in acidic environments–More readily absorbed–Less susceptible to deactivation–Active against more types of bacteriaInhibition 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• Echinocandins, such as caspofungin, inhibit the enzyme that synthesizes glucanInhibition of Protein Synthesis•Recall that prokaryotic ribosomes are 70S (30S and 50S subunits) while eukaryotic ribosomes are 80S (40S and 60S subunits)–Antimicrobial agent take advantage of the differences between ribosomes to 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 animalsInhibition of Protein SynthesisDisruption of Cytoplasmic Membranes•Some drugs disrupt the cytoplasmic membrane of a targeted cell, often by forming a channel through the membrane, damaging its integrity•Bacterial membranes–Polymyxin effective against Gram-negatives; toxic to human kidneys–Reserved for use against external pathogens–Pyrazinamide disrupts transport across the cytoplasmic membrane of M. tuberculosis •Fungal membranes–Ergosterol is a lipid constituent in fungal membranes and is a target of several drugs–Humans somewhat susceptible because cholesterol similar to ergosterol–Bacteria lack sterols; not susceptibleDisruption of Cytoplasmic Membranes•Helminth membranes–Praziquantel (tapeworms) and ivermectin (roundworms) change the permeability of cell 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–Atovaquone interferes with electron transport in protozoa and fungi–Heavy metals (arsenic, mercury, antimony) 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)Inhibition of Metabolic PathwaysInhibition of Metabolic Pathways•Antiviral agents can target unique aspects of viral metabolism–Amantadine, rimantadine (both effective against influenza A), and weak organic bases neutralize acidity of phagolysosome and prevent viral uncoating–Protease inhibitors interfere with protease that HIV needs in its replication cycleInhibition of Nucleic Acid