Protein synthesis
inhibitors:
Chloramphenicol,
Tetracyclines,
Macrolides, Clindamycin
Streptogramins &
Oxazolidinones
Pawitra Pulbutr,
M.Sc. In Pharm (Pharmacology)
วัตถุประสงค์เชิงพฤติกรรม
• เข้าใจและอธิบายถึงกลไกการออกฤทธิ์, กลไกการดื้อยา, เภสัช
จลนศาสตร์, อาการไม่พงึ ประสงค์ท่เี กิดจากการใช้ยา, การนาไปใช้
ประโยชน์ทางคลินิก รวมทัง้ ข้อดีและข้อเสียของยาต้านแบคทีเรียในกลุม่
Protein synthesis inhibitors ได้แก่
chloramphenicol, tetracyclines,
macrolides, clindamycin,
streptogramins, oxazolidinones,
ketolides ได้
Bacterial protein synthesis
Drug acting as protein
synthesis inhibitors
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Chloramphenicol
Tetracyclines
Macrolides
Clindamycin
Ketolides
Oxazolidinones
Streptogramins
Aminoglycosides
Spectinomycin
Chloramphenicol
• First synthetic antibacterial
• Mechanism of action
– Bind with 50s subunit
– Inhibit peptidyl transferase
– Inhibit transpeptidation … connection of
peptide from P-site to A-site***
– Bacteriostatic
– Bactericidal to some bacteria >>>H.
influenzae, N. meningitidis, bacteroides
• Resistance
– Decrease uptake
– Chloramphenicol acetyl transferase enzyme…
destroy
Clinical uses
o Serious rickettsial infection
o Typhus … alternative to doxycycline
o Bacterial meningitis (due to PRSP,
meningococcus) … alternative to
penicillin
o Eye infection** .. Topical
o Melioidosis … Burkholderia
pseudomalleri (gram negative rods)
ADRs
• GI disturbance.. n/v, diarrhea, oral-vaginal
candidiasis
• Bone marrow supression*** … dose
dependent…> 50 mg/kg/day for 1-2 wks
• Aplastic anemia … idiosyncratic reaction… not
dose dependent … 1 in 24,000-40,000 ….
Fetal reaction
– Unexplained infection/ Bleeding/ Fatigue
• Toxicity for newborn
– Immature conjugation
– Gray baby syndrome … vomiting, flaccidity,
hypothermia, gray color, shock, death
– Not > 50 mg/kg in infants , > 25 mg in immatures
Tetracyclines
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chlortetracycline
oxytetracycline
tetracycline
demeclocycline
methacycline
doxycycline
minocycline
Hydrochloride
salt… more
water soluble
All chelates
with divalent
metal ions***
Mechanism of action
• Bind with 30 s subunit
• Inhibit binding of aminoacyl-tRNA
to A-site
• Inhibit protein synthesis
• Bacteriostatic
Spectrum
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Broad spectrum
gram positive, negative, anaerobes
rickettsiae
chlamydia
mycoplasma
protozoa (ameba, plasmodium)
Clinical uses
• DOC for Mycoplasma pneumonia,
Chlamydia, Rickettsia infection
• Acne**
• Bronchitis
• Community acquired pneumonia
• Lyme disease
• Leptospirosis**
• Vibrio infection
• Atypical mycobacterial infection
• H. pyroli infection … Gastric ulcer
• Protozoal infection** …
E. histolytica, Plasmodium (malaria)
Macrolides
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Macrocyclic lactone ring
Erythromycin
Roxithromycin
Clarithromycin
Azithromycin
Mechanism of action
• Bind 50s subunit
• Inhibit aminoacyl translocation
• Inhibit translocation of tRNA from
A-site to P-site
• Resistance
• Decrease uptake or Efflux pump
• Produce esterase enzyme … destroy
drugs
• Alteration of ribosomal binding site ….
Methylase ***… MLS-B
Clinical uses
• DOC for …
– Corynebacterium infection (diphteria*,
corynebacterial sepsis, erythasma)
– Respiratory, neonatal, ocular, genital
Chlamydial infection*
– Community acquired pneumonia
• Pneumococci
• Mycoplasma
• Legionella
Alternative to penicillin in..
• streptococci
• staphylococci
• pneumococci
• pharyngitis
• skin & soft
tissue infection
• pneumonia
Many are resistant
to macrolide too!!
Endocarditis prevention in valvular
heart disease pt undergoes dental
surgery
Ketolides
• Telithromycin
• Macrolide like … macrocyclic
lactone ring
• 3- keto group
• No L-cladinose sugar
• Macrolide like mechanism of action
• Bind to 50s subunit
• Higher affinity
Spectrum
• RTI caused by … beta-lactam,
macrolide, tetracyclines, cotrimoxazole resistant bacteria
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S. pneumoniae
H. influenzae
M. catarrhalis
Effective to MLS-B resistance***
No MLS-B inducer
Clindamycin
o Cl derivative of lincomycin
o Erythromycin like mechanism of
action… bind at 50 s subunit
o Erythromycin binding site
o Spectrum
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o
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Streptococci
Staphylococci
Pneumococci
Bacteroides & Other anaerobes***
Not effective to gram negative
(poor permeability) , enterococci,
Clostridium difficile
Streptogramins
o
o
o
o
Quinupristin-dalfopristin (Synercid®)
Quinupristin = Streptogramin B 30%
Dalfopristin = Streptogramin A 70%
Macrolide like mechanism of action …
bind at 50s subunit
o Spectrum
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Gram positive bacteria**
Multidrug resistant streptococci
Penicillin resistant pneumococci (PRSP)**
MRSA**
Enterococcus faecium (not E. faecalis)
Not to gram negative***
Clinical uses …. IV
infusion
• Vancomycin resistant E. faecium
(VRE) infection
• MRSA infection
• Streptococci infection
• Penicillin resistant/ susceptible
pneumococci infection
Oxazolidinones
• Linezolid (Zyvox®)
• Mechanism of action
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Bind at 23s rRNA of 50s subunit
Inhibit Ribosomal assembly
Unique binding site … No cross resistance
Time dependent killing
• Spectrum
– Gram positive which resistant to other
drugs
– Staphylococci, Streptococci, Enterococci
– Gram positive anaerobes, rods
– MRSA,VRE, PRSP ***
– No activity on gram negative
Clinical use
• VRE infection
• Other multidrug resistant
Tetracyclines
Bind at 30s subunit
Chloramphenicol bind at 50s
Oxazolidinones … bind at
23s rRNA
Macrolides/ Ketolides/
Clindamycin/ Streptogramins
Bind at 50s subunit