Bacterial protein synthesis inhibitorsBacterial protein synthesis inhibitorsPart 1.Part 1. Macrolides( Macrolides( 大环内酯类大环内酯类 ), Lincomycin(), Lincomycin( 林可林可

霉素类霉素类 ),),Part 2.Part 2. Aminoglycosides( Aminoglycosides( 氨基糖苷类氨基糖苷类 ) and Polymy) and Polymy

xins(xins( 多黏菌素类多黏菌素类 ))Part 3.Part 3. Tetracyclines( Tetracyclines( 四环素类四环素类 ) and Chloramphe) and Chloramphe

nicol(nicol( 氯霉素氯霉素 ))

Synthetic antimicrobial agents(Synthetic antimicrobial agents( 人工合成抗菌药人工合成抗菌药 ))

Content

Bacterial protein synthesis inhibitors

Part1-1 MacrolidesMacrolides

History1952 Erythromycin( 红霉素 )1970s Acetylspiramycin( 乙酰螺旋霉素 ) Medecamycin( 麦迪霉素 ) josamycin( 交沙霉素 )1980s Clarithromycin ( 克拉霉素 ) Roxithromycin( 罗红霉素 ) Azithromycin( 阿奇霉素 )

Macrolides

(( 红霉红霉素素 ))

(( 克拉霉克拉霉素素 ))

(( 阿奇霉阿奇霉素素 ))

STRUCTURE:

• 14 碳环大环内酯类：– 红霉素

(erythromycin) – 克拉霉素

(clarithromycin)– 罗红霉素

(roxithromycin)

• 15 碳环大环内酯类：

– 阿奇霉素 (azithromycin)

• 16 碳环大环内酯类：– 吉他霉素

(kitasamycin) – 交沙霉素 (josamycin)– 乙酰螺旋霉素

(acetylspiramycin)– 麦迪霉素

(medecamycin)

Erythromycin ( 红霉素 )

• Antimicrobial activity– Gram-positive organisms: pneumococci （肺炎双球菌

） , streptococci （链球菌） , staphylococci （葡萄球菌） , diphtheriae （白喉） etc

– Gram-negative organisms:legionella （军团菌） ,bacillus pertussis( 百日咳 ), brucella( 布氏 ) ,

meningococci （脑膜炎球菌） , diplococcus gonorrhoeae （淋病双球菌） etc

– Others: mycoplasma( 支原体 ), chlamydia trachomatis( 沙眼衣原体 ), rickettsia( 立克次体 ),

spirochete ( 螺旋体 ), anaerobes( 厌氧菌 ) etc.

Macrolides

Typical therapeutic applications of macrolides.

• Target50s ribosomal

RNA

• MechanismInhibition of

translocation of mRNA

Macrolides

C: ChloramphenicChloramphenicol ol

M: MacrolidesMacrolides

T: Tertracyclines

Mechanism of action

Pharmokinetics

• Not stable at acid pH• Metabolized in liver• Excreted in bile

Drugs:– erythromycin stearate( 硬脂酸红霉素）– erythromycin ethylsuccinate （琥乙红霉素，利君沙）– erythromycin estolate （无味红霉素）

Macrolides

Mechanism of resistance

Modification of the ribosomal binding site

Production of esterase that hydrolyze macrolides

Active efflux system

Macrolides

Adverse reactions

• Gastrointestinal effects• Liver toxicity• Superinfection( 二重感染 )

Macrolides

Second generation

• Advantage :

– Broader spectrum, higher activity– Orally effective– High blood concentration– Longer t 1/2– Less toxicity– Mainly used in respitory tract

infection

Macrolides

Azithromycin ( 阿齐霉素）

• Has the strongest activity against mycoplasma pneumoniae （肺炎支原体）

• More effective on Gram-negative bacteria

• Well tolerated• T1/2 :35~48h once daily• Mainly used in respiratory tract

infection

Macrolides

Clarithromycin （甲红霉素 , 克拉霉素）

• Has the strongest activity on Gram-positive bacteria, legionella pneumophila( 肺炎衣原体 ), chlamydia pneumoniae ( 嗜肺军团菌 )and H.p

• Good pharmacokinetic property• Low toxicity

Macrolides

Third generation • Ketolides( 酮基大环内酯类 )• Ketolides are semisynthetic 14-membered-ring

macrolides, differing from erythromycin by substitution of a 3-keto group for the neutral sugar L-cladinose.

• Telithromycin ( 泰利霉素 ) – It is active in vitro against Streptococcus pyogenes, S

pneumoniae, S aureus, H influenzae, Moraxella catarrhalis, mycoplasmas, Legionella, Chlamydia, H pylori, N gonorrhoeae, B fragilis, T gondii, and nontuberculosis mycobacteria.

– Many macrolide-resistant strains (macrolides-lincomycins-streptogramins, MLS)are susceptible to ketolides because the structural modification of these compounds renders them poor substrates for efflux pump-mediated resistance and they bind to ribosomes of some bacterial species with higher affinity than macrolides.

Macrolides

Some properties of the macrolide antibiotics.

Part 1-2 Lincomycin ( 林可霉素 )and Clindamycin （克林霉素）

Lincomycin & Clindamycin

① Chloramphenicol Chloramphenicol

② ClindamycinClindamycin MacrolidesMacrolides

③ Tertracyclines

Mechanism Binding to 50s ribosome subunit and inhibiting protein synthesis

• Antimicrobial activity– Gram-positive organisms– Bacteroide fragilis and other anaerobes

• Pharmacokinetics– Absorbed well– Penetrate well into most tissues including bone

Lincomycin & Clindamycin

• Clinical uses – Severe anaerobic infection – Acute or chronical suppurative osteomylitis （化脓

性骨髓炎） , arthritis caused by susceptive organisms especially Staphylococci aureus （金黄色葡萄球菌）

• Adverse reactions– Gastrointestinal effects: severe diarrhea and

pseudomembranous enterocolitis caused by Clostridium difficile （难辨梭状芽孢杆菌） :• vancomycin & metronidazole( 甲硝唑 )

– Impaired liver function , neutropenia( 中性粒细胞减少 )

Lincomycin & Clindamycin

Part 1-3Oxazolidinones( 恶唑烷酮类 )--- Linezolid ( 利奈唑胺 )

• Linezolid is a member of the oxazolidinones, a new class of synthetic antimicrobials.

• Mechanism of action– Linezolid inhibits protein synthesis by preventing formation

of the ribosome complex that initiates protein synthesis. Its unique binding site, located on 23S ribosomal RNA of the 50S subunit, results in no cross-resistance with other drug classes.

• Mechanism of Resistance– Resistance is caused by mutation of the linezolid binding

site on 23S ribosomal RNA.

Linezolid

• Antimicrobial spectrum:– It is active against gram-positive

organisms including staphylococci, streptococci, enterococci, gram-positive anaerobic cocci, and gram-positive rods such as corynebacteria and Listeria monocytogenes.

– It is primarily a bacteriostatic agent except for streptococci for which it is bactericidal.

– There is modest in vitro activity against Mycobacterium tuberculosis.

Linezolid

• Adverse reaction– The principal toxicity of linezolid is hematologic—reversible and

generally mild.– Thrombocytopenia( 血小板减少症 ) is the most common

manifestation (seen in approximately 3% of treatment courses), particularly when the drug is administered for longer than 2 weeks.

– Neutropenia may also occur, most commonly in patients with a predisposition to or underlying bone marrow suppression.

• Pharmacokinetics– Linezolid is 100% bioavailable after oral administration and has

a half-life of 4–6 hours. It is metabolized by oxidative metabolism, yielding two inactive metabolites.

– It is neither an inducer nor an inhibitor of cytochrome P450 enzymes. Peak serum concentrations average 18 g/mL following a 600 mg oral dose. The recommended dose for most indications is 600 mg twice daily, either orally or intraveneously.

• Clinical uses – Vancomycin-resistant E faecium infections; – nosocomial pneumonia( 医院获得性肺炎 ); – community-acquired pneumonia( 社区获得性肺炎 ); – skin infections

Linezolid

Part1-4 Streptogramins ( 链阳性菌素 )

• Streptogramins are effective in the treatment of Vancomycin-resistant Staphylococcus aureus (VRSA) and Vancomycin-resistant enterococcus (VRE), two of the most rapidly-growing strains of multidrug-resistant bacteria.

• Members include:– Quinupristin/dalfopristin ( 喹奴普丁 / 达福普丁 )– Pristinamycin – Virginiamycin – NXL 103, a new oral streptogramin currently in phase II

trials (As of). It will be used to treat respiratory tract infections.

Streptogramins

Quinupristin/dalfopristin ( 喹奴普丁 / 达福普丁 )

• A mixture of two streptogramins in a ratio of thirty to seventy, respectively.

• They are derived from a streptomycete and then chemically modified.

• The drug is normally reserved for the treatment of vancomycin-resistant Entero coccus faecium (VRE).

• Mechanism of action• Each component of this combination drug binds to a separate sit

e on the 50S bacterial ribosome, forming a stable ternary complex. Thus,they synergistically interrupt protein synthesis. The combination drug is bactericidal and has a long postantibiotic effect.

• Resistance• Enzymatic processes commonly account for resistance to these a

gents. For example, the presence of a ribosomal enzyme that methylates the target bacterial 23S ribosomal RNA site can interfere in quinupristin binding. In some cases, the enzymatic modifi cation can change the action from bactericidal to bacteriostatic. Plasmid-associated acetyltransferase inactivates dalfopristin. An active efflux pump can also decrease levels of the antibiotics in bacteria.

• Antibacterial spectrum• The combination drug is active primarily against gram-

positive cocci, including those resistant to other antibiotics (for example, methicillinresistant staphylococci).

• Its primary use is in the treatment of E. faecium ( 屎肠球菌 ) infections, including VRE strains. The drug is not eff ective against Enterococcus faecalis( 粪肠球菌 ).

Pharmacokinetics

• Quinupristin/dalfopristin is injected intravenously (the drug is incompatible with a saline medium).

• The combination drug penetrates macrophages and polymorpho nucleocytes, a property that is important, because VRE are intracellular. Levels in the CSF are low. Both compounds undergo metabolism.

• The products are less active than the parent in the case of quinupristin and are equally active in the case of dalfopristin.

• Most of the parent drugs and metabolites are cleared through the liver and eliminated via the bile into the feces. Urinary excretion is secondary.

Adverse eff ects

1. Venous irritation2. Arthralgia and myalgia: These have been reported when higherlevels of the drugs are employed.3. Hyperbilirubinemia( 高胆红素血症 ): Total bilirubin is elevated in

about 25 percent of patients, resulting from a competition with the antibiotic for excretion.

4. Interactions: • Because of the ability of quinupristin/dalfopristin to inhibit the c

ytochrome P450 (CYP3A4) isozyme, concomitant admin-istration with drugs that are metabolized by this pathway may lead to toxicities.

• A drug interaction with digoxin appears to occur by the same mechanism as that caused by erythromycin.

Let’s have a Let’s have a rest!rest!