1、Lecture 11Antimicrobial DrugsAntimicrobial Drugs Chemicals used to treat microbial infections Before antimicrobials,large number of people died from common illnesses Now many illnesses easily treated with antimicrobials However,many antimicrobial drugs are becoming less usefulAntimicrobial Drugs Che
2、motherapeutic agent=Antimicrobial drug=Different types of antimicrobial drugs:Antibacterial drugs Antifungal drugs Antiprotozoan drugs Antihelminthic drugsPaul Ehrlich He observed that certain dyes stain bacterial cells and not animal cells Theorized that there could be a dye or chemical that would
3、harm bacterial cells but not human cells Systematic search for chemical to cure syphilis 606th compound tested proved to be highly effective in treating laboratory animalsGerhard Domagk Discovered red dye,Prontosil effective in treating Streococcal infections in animals No effect in test tubes Enzym
4、es in animals blood split Prontosil molecule into sulfanilamide-this acted against streptococcal Sulfa DrugAlexander Fleming Working on cultures of Staphylococcus Contamination with mold Noticed colonies growing near mold looked odd Found that mold was secreting substance that was killing bacteriaFi
5、gure 20.1Features of Antimicrobial DrugsMost modern antibiotics come from species of microorganisms that live in the soilTo commercially produce antibiotic:1.Select strain and grow in broth2.When maximum antibiotic concentration reached,extract from medium3.Purify4.Chemical alter to make it more sta
6、bleFeatures of Antimicrobial Drugs:Selective Toxicity Cause greater harm to microorganisms than to host Chemotherapeutic index=lowest dose toxic to patient divided by dose typically used for therapyFeatures of Antimicrobial Drugs:Antimicrobial Action Bacteriostatic:inhibit growth of microorganisms B
7、actericidal:Kill microorganismsFeatures of Antimicrobial Drugs:Spectrum of Activity Antimicrobial medications vary with respect to the range of microorganisms they kill or inhibit Some kill only limited range:Narrow-spectrum antimicrobial While others kill wide range of microorganisms:Broad-spectrum
8、 antimicrobialFeatures of Antimicrobial Drugs:Effects of Combining Drugs Combinations are sometimes used to fight infections Synergistic:action of one drug enhances the activity of another Antagonistic:activity of one drug interferes with the action of anotherFeatures of Antimicrobial Drugs:Adverse
9、Effects1.Allergic Reactions:some people develop hypersensitivities to antimicrobials2.Toxic Effects:some antimicrobials toxic at high concentrations or cause adverse effects 3.Suppression of normal flora:when normal flora killed,other pathogens may be able to grow to high numbersFeatures of Antimicr
10、obial Drugs:Resistance to Antimicrobials Some microorganisms inherently resistant to effects of a particular drug Other previously sensitive microorganisms can develop resistance through spontaneous mutations or acquisition of new genesMechanisms of action of Antibacterial Drugs1.Inhibit cell wall s
11、ynthesis2.Inhibit protein synthesis3.Inhibit nucleic acid synthesis4.Injury to plasma membrane5.Inhibit synthesis of essential metabolitesFigure 20.2b-Lactam Drugs-inhibit cell wall synthesis Irreversibly inhibit enzymes involved in the final steps of cell wall synthesis These enzymes mediate format
12、ion of peptide bridges between adjacent stands of peptidoglycan b-lactam ring similar in structure to normal substrate of enzyme Drug binds to enzyme,competitively inhibit enzymatic activityb-Lactam Drugs Some bacteria produce b-lactamase-enzyme that breaks the critical b-lactam ring b-lactam drugs
13、include:penicillins and cephalosporinsAntibacterial medications that inhibit protein synthesis Target ribosomes of bacteria Aminoglycosides:bind to 30S subunit causing it to distort and malfunction;blocks initiation of translation Tetracyclines:bind to 30S subunit blocking attachment of tRNA Macroli
14、des:bind 50S subunit and prevents continuation of protein synthesisFigure 20.4bAntibacterial medications that inhibit nucleic acid synthesis Target enzymes required for nucleic acid synthesis Fluoroquinolones:inhibit enzymes that maintain the supercoiling of closed circular DNA Rifamycins:block prok
15、aryotic RNA polymerase from initiating transcriptionAntibacterial medications injure plasma membrane Polymyxin B:binds to membrane of G-bacteria and alters permeability This leads to leakage of cellular contents and cell death These drugs also bind to eukaryotic cells to some extent,which limits the
16、ir use to topical applications Antibacterial drugs that inhibit synthesis of essential metabolites Competitive inhibition by substance that resembles normal substrate of enzyme Sulfa drugsAntiviral Drugs Very few antiviral drugs approved for use in US Effective against a very limited group of diseas
17、es Targets for antiviral drugs are various points of viral reproductionNucleoside and Nucleotide analogs Acyclovir-used to treat genital herpes Cidofovir-used for treatment of cytomegaloviral infections of the eye Lamivudine-used to treat Hepatitus BAntiretrovirals Currently implies,a drug used to t
18、reat HIV Tenofovir-nucleotide reverse transcriptase inhibitor Zidovudine-nucleoside analogOther enzyme inhibitors Zanamivir(Relenza)and Oseltamivir phosphate(Tamiflu)-inhibitors of the enzyme neuominidase Used to treat influenza Indinavir-protease inhibitorsInterferons Cells infected by a virus ofte
19、n produce interferon,which inhibits further spread of the infection Alpha-interferon-drug for treatment of viral hepatitis infectionsAntifungal drugs More difficult to find point of selective toxicity in eukaryotes than in prokaryotes Targets of antifungal drugs:Agents affecting fungal sterols Agent
20、s affecting fungal cell walls Agents inhibiting nucleic acidsAgents affecting fungal sterols Many antifungals target the sterols in the plasma membrane Polyenes-used in systemic fungal infections,very toxic to kidneys Azoles-used for athletes foot and vaginal yeast infections(miconizole)Agents affec
21、ting fungal cell walls primary target of selective toxicity is-glucan Inhibition of synthesis of this glucan results in an incomplete cell wall,and results in lysis of the cell Caspofungin-first new class of antifungals in 40 yearsAgents inhibiting nucleic acids Flucytin-nucleotide analog of cytosin
22、e,interferes with the biosynthesis of RNA,and therefore protein synthesis Antiprotozoan drugs Quinine still used to control malaria Chloroquinone-synthetic derivative has largely replaced it Mefloquinone-used in areas where resistance to chloroquinone has developed Quinacrine-drug of choice for trea
23、ting protozoan disease,giardiasisAntihelminthic drugs Praziquantel-used in treatment of tapeworms;kills worms by altering permeability of plasma membranesKirby-Bauer method for determining drug susceptibility1.Bacteria spread on surface of agar plate2.12 disks,each with different antimicrobial drug,
24、placed on agar plate3.Incubated-drugs diffuse outward and kill susceptible bacteria4.Zone of inhibition around each disk5.Compare size of zone to chartFigure 21.10Resistance to antimicrobial drugs Drug resistance limits use of ALL known antimicrobials Penicillin G:first introduced,only 3%of bacteria
25、 resistant Now,over 90%are resistantHow do bacteria become resistant?1.Spontaneous Mutation:happen as cells replicate2.Gene Transfer:Usually spread through conjugative transfer of R plasmidSlowing the emergence and spread of antimicrobial resistance1.Responsibilities of Physicians:must work to ident
26、ify microbe and prescribe suitable antimicrobials,must educate patients2.Responsibilities of Patients:need to carefully follow instructions Slowing the emergence and spread of antimicrobial resistance3.Educate Public:must understand appropriateness and limitations of antibiotics;antibiotics not effe
27、ctive against viruses4.Global Impacts:organism that is resistant can quickly travel to another country-in some countries antibiotics available on non-prescription basis-antibiotics fed to animals can select for drug-resistant organismsNew Approaches to Antibiotic Therapy Are Needed Scientists work to find new antibiotic targets in pathogens Discovery of new and unique antibiotics is necessary
