Biomedical Engineering Reference
In-Depth Information
action, as it disrupts several functions of the bacterial plasma membrane without penetrating into
the cytoplasm. The insertion of daptomycin into the cytoplasmic membrane bilayers is calcium-
dependent. In the presence of calcium, daptomycin readily forms aggregates. Its concentration in the
membrane causes leakage leading to cell death. The oxazolidinones (i.e., linezolid) are active against
Gram-positive pathogenic bacteria (including MRSA) and inhibit bacterial translation at the initiation
phase of protein synthesis. It binds to the 50 S subunit and inhibits the interaction with the 30 S sub-
unit. Retapamulin is a semisynthetic pleuromutilin, a natural product of the fungi
Pleurotus mutilis
.
It is active against
S. aureus
and
S. pyogenes
and used for the treatment of impetigo. Retapamulin
inhibits bacterial protein synthesis by binding to the bacterial ribosomal 50 S subunit. Its binding site
is different from that of the classical ribosome-binding antibiotics (Figure 25.20).
During the last decennium, successful drug classes, like b-lactams (ceftazoline, ceftobiprole),
tetracyclines (tigecycline), macrolides (cetromycin), and trimethoprim (iclaprim) have been modi-
i ed by introduction of additional target binding sites, so that the compounds become active against
resistant strains. Other possibilities to obtain improved antibiotics are the synthesis of hybrids of
two antibiotic pharmacophores, the development of multitargeted antibiotics, and the combination
therapy.
During the last two decennia, several discoveries and new technologies that could increase the
likelihood of identifying new antibiotics or antibiotic targets became available. Examples are combi-
natorial library synthesis (i.e., the automatic synthesis of complex oligosaccharides), new screening
methods, the availability of bacterial genome sequences, a better understanding of the host immune
system, natural product screening, the discovery of riboswitches, and the availability of more x-ray
structure of bacterial proteins. Despite this, however, the main target for antibiotic development
is still not altered and includes DNA replication, cell-wall biosynthesis, ribosomal RNA function,
and membrane functions. It seems that the use of other antibacterial targets mainly leads to anti-
biotics with a narrow spectrum and that targeting multiple enzymes will be needed together with
the development of new chemistries (from natural or bioengineering origin). The de novo design
of multiple-targeted antibiotics for monotherapy is a difi cult process. An alternative is to target
functions, essential for infection, such as bacterial virulence factors or disrupting the interactions
between the host and the pathogen (with lesser risk to develop antibiotic resistance). Improvement
of the treatment of bacterial infections might also be expected when the antibiotic is combined with
a compound that inhibits the mechanisms of persistence.
Antibiotic resistance is presently a serious problem in the i ght against bacterial infections. Three
types of resistance mechanism can be distinguished: (a) natural or intrinsic resistance; (b) mutational
O
L
-Asp
D
-Ala
L
-Asp
Gly
D
-Ser
O
N
N
O
L
-Om
Gly
L
-Thr
OC
O
L
-Kyn
3-MeGlu
O
F
NH
C
CH
3
Linezolid
L
-Asp
L
-Asn
N
L
-Trp
OH
S
O
NH
C
O
O
H
Daptomycin
Retapamulin
O
FIGURE 25.20
Daptomycin, linezolid, and retapamulin.
