Professional Documents
Culture Documents
O
H
R C N H H
S
N OAc
O
CO2H
1. Introduction
H H H
S
R N H H H
R N S
7
O -CH3CO2-
N O Me O
O C N
O
CO2H O
O
CO2H
OH Ser
Ser Enzyme
Enzyme
• The acetoxy group acts as a good leaving group and aids the
mechanism
The Cephalosporins
H H H H H H
N S N S
7
S O 3 S O
N OAc N OH
O Metabolism O
CO2H CO2H
Less active
OH is a poorer leaving group
Strategy
• Replace the acetoxy group with a metabolically stable leaving
group
8. First Generation Cephalosporins
Cephaloridine
H H H
N S
7
S O 3
N N
O
CO2
CO2H
Cefazolin
Cefadroxil
NH2
H
N S
O
N
O CH 3
CO2Na
Cefalexin
First Generation Cephalosporins include Cefazolin (parenteral) as well as
cefadroxil and cephalexin (oral).
H OMe H S
HO2C N
H 2N H
O
Cephamycin C
N O NH2
O C
CO2H O
S O
7
Cefoxitin
N 3 O NH2
O C
CO2H O
CO2H O
OCH 3
N
O
H
N S
OCH 3 O
N N O NH2
O
H O C
N H2
S
O
O O
O
N O NH2
O C H3C O
H2
CO2Na O
O CH3
Cefuroxime
(ZINACEF) Cefuroxime axetil
(CEFTIN)
The Second-generation cephalosporins include Cefotetan, cefoxitin, and
cefuroxime (all parenteral) as well as Cefaclor, cefprozil, cefuroxime axetil, and
loracarbef (all oral).
O
N
H H
N
H
S Ceftazidime
C
S
N O
N N
H 2N O
CO2
• Injectable cephalosporin
• Excellent activity vs. P. aeruginosa and other Gram -ve
bacteria
• Can cross the blood brain barrier
• Used to treat meningitis
The Third-generation Cephalosporins include Cefotaxime, ceftazidime, ceftizoxime,
and ceftriaxone (all parenteral) as well as Cefdinir, cefditoren, cefpodoxime proxetil,
ceftibuten, and cefixime (all oral).
S O
N
O R Cefpirome
CH2 N
CO2H
• Zwitterionic compounds
• Enhanced ability to cross the outer membrane of Gram
negative bacteria
• Good affinity for the transpeptidase enzyme
• Low affinity for some -lactamases
• Active vs. Gram +ve cocci and a broad array of Gram -ve
bacteria
• Active vs. P. aeruginosa
Fourth Generation Cephalosporins include cefepime (parenteral).
Atypical bacteria
Newer b-Lactam Antibiotics
Thienamycin (Merck 1976)(from Streptomyces cattleya)
Acylamino side Opposite
chain absent stereochemistry
OH to penicillins
Plays a role H Carbon
in ß-lactamase H
resistance
H3C NH3
S
N
O
Double bond leading to
CO2 high ring strain and an increase
in -lactam ring reactivity
Carbapenam nucleus
• Potent and wide range of activity vs Gram +ve and Gram -ve
bacteria
• Active vs. Pseudomonas aeruginosa
• Low toxicity
• High resistance to -lactamases
• Poor stability in solution (ten times less stable than Pen G)
Newer b-Lactam Antibiotics
Thienamycin analogues used in the clinic
NH
H OH HN
H
Me
S Imipenem
N
O
CO2
O
H
N C
H OH H N
Me
H
Me
Me Meropenem
S
N
O
CO2
O
H
N C
H OH Me N
H
H
Me
Ertapenem(2002)
S
N
O CO2
CO2
The Carbapenems include Imipenem/cilstatin, Meropenem, and Ertapenem (all
parenteral)
Me
Me CO2H
O
N
H Me
N N
H2N Aztreonam
S O N
O SO3-
Gram-positive
bacteria
Atypical bacteria
Vancomycin
• http://student.ccbcmd.edu/courses/bio141/
lecguide/unit2/control/vanres.html
Mechanism of Action of Vancomycin
Gram-negative
bacteria
Atypical bacteria
Daptomycin
Atypical
Rifamycins
Gram-positive Staphylococci
bacteria
Anaerobic
bacteria
Anaerobic
bacteria
Atypical bacteria
Anaerobic
bacteria
Atypical Chlamydia spp. Mycoplasma spp.
bacteria Legionella pneumophila, Some
Rickettsia spp.
Mycobacteria Mycobacterium avium complex,
Mycobacterium leprae.
Spirochetes Treponema pallidum, Borrelia
burgdorferi.
Uses of Telithromycin (a ketolide)
• Telithromycin is approved for use against
bacterial respiratory infections
• Active against most strains of
Streptococcus pneumoniae, including
penicillin- and macrolide-resistant strains
• Also active against more strains of
Staphylococci
• Only available in oral formulation
The related ketolide class consists of Telithromycin (oral).
Anaerobic
bacteria
Tetracycline Tigecycline
Doxycycline
Mechanism of Action of the
Tetracycline Antibiotics
• The tetracyclines bind to the 30S subunit
of the bacterial ribosome and prevent
binding by tRNA molecules loaded with
amino acids.
• http://student.ccbcmd.edu/courses/bio141/
lecguide/unit2/control/tetres.html
Uses of the Tetracycline Antibiotics
• Main use is against atypical bacteria,
including reckettsiae, chlamydiae, and
mycoplasmas
• Also active agains some aerobic Gram-
positive pathogens and some aerobic
Gram-negative bacteria
The Tetracycline Class of Antibiotics consists of Doxycycline and
Tigecycline (parenteral) as well as Tetracycline, Doxycycline and
Minocycline (oral)
Atypical bacteria
Streptogramins
Mechanism of Action of
Streptogramins
Anaerobic
bacteria
Atypical bacteria
The Oxazolidinones
Anaerobic
bacteria
Atypical bacteria
The Sulfa Drugs
•Most commonly used sulfa drug is a mixture of the sulfa drug
Sulfamethoxazole and Trimethoprim
•These two drugs work in synergy, with the combination being superior to
either drug alone.
•This combination is known as co-trimoxazole, TMP-sulfa, or TMP-SMX
NH2
H2
C OCH3
N
H2N N OCH3
OCH3
Sulfamethoxazole Trimethoprim
Mechanism of Activity of Sulfa
Drugs
• Trimethoprim-sulfamethoxazole works by
preventing the synthesis of
tetrahydrofolate (THF), an essential
cofactor for the metabolic pathways that
generate deoxynucleotides, the building
blocks of DNA.
Tetrahydrofolic Acid Biosynthetic Pathway
• In the first step of the pathway, the sulfonamides are mistaken for the
natural substrate, p-aminobenzoic acid (PABA) and the drug acts as a
competitive inhibitor of this enzyme
• In a later step, the trimethoprim acts as a structural analog of dihydrofolate
and therefore inhibits dihydrofolate reductase
Structural Resemblance of Sulfamethoxazole and p-Aminobenzoic Acid
OH
H2N
O O
S
H2N NH2
Dapsone
Structural Comparison of Two Sulfa
Drugs
The Antimicrobial Activity of the Sulfa Drugs
Anaerobic
bacteria
Atypical bacteria
N N N N
N N
HN N O
HN Et CH3
O O
O
F CO2H F CO2H
F CO2H
N N N N
N N
NH O NH O
N O H3C
H3C
CH3
Gram-positive
bacteria
Gram-negative
bacteria
Atypical bacteria
Antimicobacterial Agents
• Mycobacterial infections are very slow
progressing
• Many antibiotics have poor activity against
slow growing infections
• Mycobacteria must be treated for a long
time, and therefore, may readily develop
resistance to a single antibiotic
• Typically, several antibiotic agents are
used simultaneously
Antimycobacterial Agents
Pyrazinamide
Rifampin
CH2OH
H
N
N
H
CH2OH
Ethambutol
Mycobacterial Infections
http://www.nature.com/nrmicro/animation/imp_animation/index.html
http://web.uct.ac.za/depts/mmi/lsteyn/cellwall.html
Mycolic Acids provide protection
• Mycolic acids are long fatty acids found in the cell walls
of the mycolata taxon, a group of bacteria that includes
Mycobacterium tuberculosis, the causative agent of the
disease tuberculosis. They form the major component of
the cell wall of mycolata species.