1、Microbiology: Principles and Explorations Sixth Edition,Chapter 13: Antimicrobial Therapy,Copyright 2005 by John Wiley & Sons, Inc.,Jacquelyn G. Black,Antimicrobial Agents,A special group of chemotherapeutic agents used to treat diseases caused by microbesAntibiosis: literally means “against life”An
2、tibiotic: A chemical substance produced by microbes which has the capacity to inhibit or destroy the growth of bacteria/other microbesSynthetic/semi-synthetic drugs,1910: Paul Ehrlich used Salvarsan to treat syphilis1935: Gerhard Domagk discovered prontosil, a red dye, inhibits growth of many gram-p
3、ositive bacteria1936: Ernest Fourneau discovered that the sulfanilamide portion contained antimicrobial activity,The History of Chemotherapy,Selective ToxicityThe Spectrum of ActivityModes of ActionSide EffectsThe Resistance of Microorganisms,General Properties of Antimicrobial Agents,The antimicrob
4、ial agent must harm the microbes without causing significant damage to the hostToxic dosage level: causes host damageTherapeutic dosage level: successfully eliminates the pathogenic organism if the level is maintained,Selective Toxicity,The range of different microbes against which an antimicrobial
5、agent actsBroad spectrum: Agents effective against both gram-positive and gram-negative bacteriaNarrow spectrum: Agents effective against a small number of microbes,Spectrum of Activity,Spectrum of Activity,Inhibition of cell wall synthesisDisruption of cell-membrane functionInhibition of protein sy
6、nthesisInhibition of nucleic acid synthesis5. Action as antimetabolites,Modes of Action,Modes of Action,Inhibiting cell wall synthesis selectively damages bacterial and fungal cellsPenicillin and cephalosporin contain a structure called a -lactam ringThe -lactam ring attaches to the enzymes that cro
7、ss-link peptidoglycans and prevent cell wall synthesis,Inhibition of Cell Wall Synthesis,Bacteria Before Exposure to Penicillin,Bacteria After Exposure to Penicillin,Certain polypeptide antibiotics, such as polymyxinsAct as detergents and distort bacterial cell membranesBind to phospholipids in the
8、membraneEspecially effective against gram-negative bacteria which have an outer membrane,Disruption of Cell Membrane Function,An example of selective toxicityAttack bacterial cells without significantly damaging animal cellsAminoglycoside antibiotics: Tetracycline, Erythromycin, streptomycin, chlora
9、mphenicolBind to the bacterial 30S ribosomal subunit and interfere with the translation of mRNA,Inhibition of Protein Synthesis,Differences between the enzymes used by bacterial and animal cells to synthesize nucleic acidsAntibiotics of the rifamycin family bind to a bacterial RNA polymerase and inh
10、ibit RNA synthesis,Inhibition of Nucleic Acid Synthesis,Substances that affect the utilization of metabolites and prevent metabolic reactionsFunction in two ways:Competitively inhibiting enzymes Erroneously incorporated into important molecules such as nucleic acids,Action as Anti-metabolites,Compet
11、itive Inhibition,Nucleic Acid Base Analogs,The side effects of antimicrobial agents fall into three general categories:ToxicityAllergyDisruption of normal microbiota,Kinds of Side Effects,Acquisition of Resistance,Microorganisms normally acquire antibiotic resistance by genetic changes:Natural Selec
12、tionChromosomal MutationExtrachromosomal Resistance R Plasmids or R factors,Method of Detecting Genetic Resistance,Alteration of TargetsAlteration of Membrane PermeabilityDevelopment of EnzymesAlteration of an Enzyme5. Alteration of a metabolic pathway,Mechanisms of Resistance,b-lactamase Effect on
13、Penicillin,This mechanism usually affects bacterial ribosomesThe mutation alters the DNA such that the protein produced or target is modifiedAntimicrobial agents can no longer bind to the targetResistance to erythromycin, rifamycin, and anti-metabolites,Alteration of Targets,B-lactamaseThese enzymes
14、 are found in various bacteriaThey catalyze the breaking of the B-lactam ring in penicillins and some cephalosporins,Enzyme Development,First-Line, Second-Line Third-Line Drugs,1930s sulfonamides were found to cure the disease, gonorrheaSulfonamide-resistant strains developed and penicillin was used
15、 as a curePenicillin-resistant strains developed and spectinomycin was used Now there are spectinomycin-resistant strains of gonorrhea,Effects of Premature Termination of Antibiotic Treatment,Kirby-Bauer Method of Determining Microbial Sensitivities to Various Antibiotics,Minimal Inhibitory Concentr
16、ation (MIC) Microbial Susceptibility,An Epsilometer (E) Test for Determining Antibiotic Sensitivity,Inoculating Samples Into Individual Wells Containing Specific Chemical Agents,Incubator Chamber,Structures of Penicillin and Related Molecules,Staining of Teeth by Tetracycline,Red Man Syndrome,Agents
17、 That Inhibit Protein Synthesis,Agents That Inhibit Nucleic Acid Synthesis,Agents That Inhibit Cell Wall Synthesis,Agents That Interfere With Cell Membrane Function,Antimetabolites and Other Agents,Black Hairy Tongue: A Reaction to Metronidazole (Flagyl),Antifungal Agents,Antihelminthic Agents,Antiv
18、iral Agents,Antiprotozoan Agents,Disrupters of Cell Membranes,Polymyxins (A, B, C, D, and E)Obtained from soil bacterium Bacillus polymyxaUsually applied topically, often with bacitracin, to treat skin infections caused by PseudomonasInternally, can cause numbness in the extremities, serious kidney
19、damage, and respiratory arrest,Tetracyclines,Obtained from species of StreptomycesAre bacteriostatic, readily absorbed from the digestive tract, and become widely distributed in tissues and body fluidsHave the widest spectrum of activity of any antibioticsHowever, they destroy the normal intestinal
20、microbiota and ofter produce severe gastrointestinal disorders,Interferons and Immunoenhancers,Cells infected with viruses produce proteins collectively referred to as interferonsThese interferon proteins induce neighboring cells to produce antiviral proteinsAntiviral proteins prevent these cells from becoming infectedInterferons are currently being genetically engineered and tested as antiviral agents,Double Antibiotic Therapy To Eradicate Resistant Strain Infections,
