《药理学》课程PPT教学课件（Antimicrobial Drugs）41 Aminoglycosides

Aminoglycosides氨基糖武类

Aminoglycosides 氨基糖甙类

1.OverviewAminoglycosides氨基糖武类·areinhibitors of proteinsynthesis,butarebactericidal杀菌·areactiveagainstgram(-）bacteria and someMycobacteria 分支杆菌·havetheir actionenhanced by inhibitors of cell wall synthesis细胞壁合成抑制剂·aretoxicfortheear耳朵andkidney肾,andhavea lowTIproteinsynthesisgram(-)inhibitorribosomeactivityenhancedbyinhibitorof cellwallsynthesisbactericide

1. Overview Aminoglycosides 氨基糖甙类 •are inhibitors of protein synthesis, but are bactericidal 杀菌 •are active against gram(-) bacteria and some Mycobacteria 分支杆菌 •have their action enhanced by inhibitors of cell wall synthesis 细胞壁 合成抑制剂 •are toxic for the ear 耳朵 and kidney 肾, and have a low TI

Position of AminoglycosidesAminoglycosidesarederivedfromStreptomyces(drugsserious,systemicending with"-mycin")-andinfections of:Micromonosporaorganisms(drugs in"-micin")lungsThey were extensively usedbloodbefore the advent of other,safer, drugs active on gram(-)abdomeninfections:3rd-generationcephalosporins头孢菌素，urinary tractfluoroquinolones氟喹诺酮类，imipenemBecauseoftheir toxicity,theyarenowreserved only for seriousandunresolved infections of the blood (septicemia), abdomen, urinarytract,andlungs,usuallyinassociationwithapenicillin盘尼西林orcephalosporin头孢菌素

Position of Aminoglycosides Aminoglycosides are derived from Streptomyces (drugs ending with “-mycin”) -and Micromonospora organisms (drugs in “-micin”) They were extensively used before the advent of other, safer, drugs active on gram(-) infections: 3rd-generation cephalosporins 头孢菌素, fluoroquinolones 氟喹诺酮类, imipenem Because of their toxicity, they are now reserved only for serious and unresolved infections of the blood (septicemia), abdomen, urinary tract, and lungs, usually in association with a penicillin 盘尼西林 or cephalosporin 头孢菌素

Aminoglycosides vs. Other Drugswater-soluble drugslipophilic drugsnarrow-wallvspectrumGram+porinsXpenicillinsouterVXmembrane盘尼西林类thick cell wallmacrolidesextended-大环内酯类wallvspectrumotherporinsvpenicillinsinfectiousouteragentsmembraneGram-fluoroquinolonestetracyclineswallX氟睦诺酮类thin cell wall四环素类porinsaminoglycosideschloramphenicolcomplexoutermembrane氨基糖类氯霉素+ someMycoplasmaSporins1

Aminoglycosides vs. Other Drugs + some Mycoplasma

Molecular StructuresCH2OHHN?HOCH2NH2H2NOHH2NHlHONH2OHONH2HOCNH2HOHNgentamicinOHtobramycinNH2Aminoglycosides contain aminosugars 氨基糖andarehighlywater-soluble水溶性

Molecular Structures Aminoglycosides contain aminosugars 氨基糖 and are highly water-soluble 水溶性

DrugsStreptomycin链霉素andamikacin阿米卡星werefirstusedStreptomycin is still used against tuberculosis 肺结核Gentamicin庆大霉素andtobramycin托普霉素aremoreusedtodayNeomycin新霉素ismainlyusedtopically

Drugs Streptomycin 链霉素 and amikacin 阿米卡星 were first used Streptomycin is still used against tuberculosis 肺结核 Gentamicin 庆大霉素 and tobramycin 托普霉素 are more used today Neomycin 新霉素 is mainly used topically

Mechanism of ActionbindingoftRNAAAat the A siteaccordingtotheAAcodon-anticodonrecognitionAAAAthe P sitecontains theprotein informationantianticodoncodoncodoncodonPAMostmacrolides irreversiblybindto the3oS ribosomesubunit,andinterfere with codon-anticodon recognition. The irreversibility mayexplain the bactericide activity, as well as a post-antibiotic effect

Mechanism of Action Most macrolides irreversibly bind to the 30S ribosome subunit, and interfere with codon-anticodon recognition. The irreversibility may explain the bactericide activity, as well as a post-antibiotic effect

EntryintoBacteriaDiffusionthroughtheToo water-porins of thesoluble toGram +Gram-outercrossthethin cell wallmembranethick cell wallinnercomplexoutermembrane(Nakae&Nakae1982)membranewellporinsPassagethroughtheinnerInhibitorsofcellwallmembranedependingonsynthesisfacilitate entry,andpolarization,andthereforeoxygenpotientiate actionMostlyactiveagainstgram(-)，andneveragainstanaerobes厌氧微生物.Used in combination with cell wall inhibitor against gram(+)

Entry into Bacteria •Mostly active against gram(-), and never against anaerobes 厌氧微生物 •Used in combination with cell wall inhibitor against gram(+) Too water￾soluble to cross the inner membrane well Inhibitors of cell wall synthesis facilitate entry, and potientiate action Diffusion through the porins of the outer membrane (Nakae & Nakae 1982) Passage through the inner membrane depending on polarization, and therefore oxygen

Spectrum and Uses of AminoglycosidesAminoglycosides arestreptomycinStaphilococcitobramycinEnterococciactive against mostgram(-) bacteriagram+In associationcocciwith a cell wallThey are also activeinhibitor, inagainstStaphylococci, andsevere casescan be activeagainst Enterococcigram-when combined withurinary tractenteiicotherEnterobacter infectionsrodspenicillinsgram-Escherichia colibacillipneumoniaTheyhavenoKlebsiella pneumoniaeVibrio choleraeactivity againstYersinia pestisanaerobic bacteriaPseudomonas aeruginosabecause their entryFrancisella tularensisintothebacterialcell depends onoxygenPlague瘟疫，tularemia野兔病，Pseudomonasaeruginosa假单胞菌infections

Spectrum and Uses of Aminoglycosides Aminoglycosides are active against most gram(-) bacteria They are also active against Staphylococci, and can be active against Enterococci when combined with penicillins They have no activity against anaerobic bacteria because their entry into the bacterial cell depends on oxygen In association with a cell wall inhibitor, in severe cases Plague 瘟疫, tularemia 野兔病, Pseudomonas aeruginosa 假单胞菌 infections

Resistance toAminoglycosidesResistance results from:.acquisition of plasmid-coded enzymes inactivating the drugs.alteredtransportintobacteria.mutationalteringtheribosome酶enzyimesalteredentry外部的细胞膜核糖体modifiedribosome

Resistance to Aminoglycosides Resistance results from: • acquisition of plasmid-coded enzymes inactivating the drugs • altered transport into bacteria • mutation altering the ribosome 酶 外部的细胞膜 核糖体