Antibacterial and antifungal vaccines based on synthetic oligosaccharides - Carbohydrate Chemistry: Chemical and Biological Approaches - page 582

urinary tract infections. Such infections involve millions of cases world-
wide and cause high mortality despite heavy antibiotic use. 141 There is a
possibility that hospital-acquired infections may be controlled by
immunopreventive or immunotherapeutic interventions. Thus, the de-
velopment of therapeutic monoclonal antibodies to kill the bacteria or a
vaccine to prevent these diseases is highly desirable.

4.1 Staphylococcus aureus
S. aureus, a Gram-positive bacterium, is a major cause of nosocomial and
community-acquired infections. 142 In recent years, the development of
community-associated methicillin-resistant S. aureus has complicated
treatment options. Previously healthy individuals are at risk for infection
with this pathogen.
For several years, StaphVAX was among the conjugate vaccines under
development. It is composed of the CPS of serotypes 5 and 8 conjugated
to recombinant exoprotein A from Pseudomonas aeruginosa. In clinical
studies, the vaccine generated a robust immune response to both CPS5
and CPS8, but did not significantly reduce nasal colonization rates. 143
In a search for new vaccine antigens, the partially acetylated form of
the b-(1

6)-poly- D -glucosamine polysaccharide 39 was found to be cru-
cial for the virulence of bacterial biofilms produced by coagulase-negative
strains. 144 Protective antibodies to 39 are elicited when a deacetylated
glycoform ( o 30% acetyl) is used in conjugate vaccines, whereas highly
acetylated 39 does not induce such antibodies (Scheme 13). 145
Controlled deacetylation of native PS at a given position is very ine-
cient, so in this particular case, synthetic oligosaccharides are of para-
mount

-

6)-linked oligomers were
performed having either N-acetyl or NH 2 groups. 146 The ecient synthesis
of fragments up to nonamer was accomplished. 147 Synthetic fragments
(GlcNH 2 ) 5 -TT, (GlcNAc) 5 -TT, (GlcNH 2 ) 9 -TT 40 and (GlcNAc) 9 -TT conjugates
were used to immunize mice. Antibodies against GlcNH 2 -containing con-
jugates mediated opsonic killing of multiple S. aureus strains. Notably,
rabbit antibodies to 40 mediated killing of S. aureus and E. coli,andpro-
tected against S. aureus skin abscesses and lethal E. coli peritonitis.
Further simplification of the synthesis for this promising vaccine
candidate was conducted with a simpler N-trifluoroacetamido-glucose
derivative that allows the synthesis of a pentasaccharide in seven steps in
an overall yield of 25%. 148

importance. The synthesis of b-(1 -

Scheme 13