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Anti-Infective
Agents in Medicinal Chemistry
ISSN: 1871-5214
Anti-Infective Agents in Medicinal
Chemistry
Volume 6, Number 2, April 2007
Contents
Burkholderia pseudomallei - Antimicrobial
Susceptibility Testing and Alternative Models of Predicting
Clinical Efficacy Pp. 83-88
Robert Norton
[Abstract]
Mass Spectrometry, Proteomics, Data Mining Strategies
and Their Applications in Infectious Disease Research
Pp. 89-105
Andreas Evangelou, Limor Gortzak-Uzan, Igor Jurisica and
Thomas Kislinger
[Abstract]
Aminoglycosidic Aminocyclitol Antibiotics-A Wonder,
But Toxic Drugs: Developments and Clinical Implications
Pp. 107-117
M. Shahid
[Abstract]
Inactivation of Pathogenic Microorganisms by Photodynamic
Techniques: Mechanistic Aspects and Perspective Applications
Pp. 119-131
Giulio Jori and Olimpia Coppellotti
[Abstract]
Medicinal Use of Lincosamides and Microbial Resistance
to Them Pp. 133-144
Tomáš Rezanka, Jaroslav Spížek
and Karel Sigler
[Abstract]
Revitalized Strategies Against Multi-Resistant Bacteria:
Antimicrobial Photodynamic Therapy and Bacteriophage Therapy
Pp. 145-150
Tim Maisch
[Abstract]
Abstracts
[Back to top]
Burkholderia pseudomallei - Antimicrobial Susceptibility
Testing and Alternative Models of Predicting Clinical Efficacy
Robert Norton
Melioidosis is caused by the gram-negative bacterium Burkholderia
pseudomallei. The disease can present with a diverse
range of clinical manifestations and is endemic in northern
Australia and Southeast Asia. There is a dramatic increase
in clinical cases during the wet season and mortality rates
remain as high as 70% in some endemic areas. This is despite
current optimal treatment with ceftazidime or meropenem, with
trimethoprim-sulfamethoxazole.. This highlights the need for
studies into novel antimicrobials or adjunctive therapies.
There are currently no CLSI disc diffusion susceptibility
criteria for this organism. A comparative study looking at
methods of susceptibility testing for B. pseudomallei
showed that an MIC based method is required to test susceptibility
against trimethoprim-sulfamethoxazole. CLSI MIC breakpoints
for this organism are available. In-vitro susceptibility
testing to alternative antimicrobials has also been done for
ertapenem, moxifloxacin and tigecycline. Recently, a BALB/c
mouse model of melioidosis has been used to investigate strategies
for antimicrobial therapy. Combination therapy with ceftazidime
and trimethoprim-sulfamethoxazole has been found to be most
efficacious. The use of granulocyte colony stimulating factor
as adjunctive therapy has also been studied and shown to be
of little value in this model. Similar studies are planned
for the novel glycylcycline tigecycline. An Acanthamoeba intracellular,
broth microdilution, model for B. pseudomallei has
also been developed. This showed elevated MICs to both meropenem
and ceftazidime when compared with standard MIC determination.
Both these alternative models provide us with a unique opportunity
to further our knowledge in several key aspects of an important
tropical infectious disease.
[Back to top]
Mass Spectrometry, Proteomics, Data Mining Strategies
and Their Applications in Infectious Disease Research
Andreas Evangelou, Limor Gortzak-Uzan, Igor Jurisica and
Thomas Kislinger
The ultimate goal of proteome research is the comprehensive
description of all proteins present in a given sample using
qualitative, quantitative and functional metrics. Traditionally,
protein mixtures were first separated by two-dimensional gel
electrophoresis and spots of interest were excised, in-gel
digested and analyzed by mass spectrometry (MS). In most cases,
protein identification was done by MALDI-TOF-MS (matrix-assisted
laser desorption/ionization time-of-flight). The methodology
is time consuming and rarely leads to a comprehensive description
of the analyzed proteome. Over the last years shot-gun expression
profiling methodologies were developed and can identify thousands
of proteins in complex biological samples in a single experiment.
We will provide a short historic overview of proteome research
and mass spectrometry technologies currently used in the systems
biology community. In particular, we will summarize the developments
and applications of shot-gun proteomics and allied computational
data mining tools to medical research and infectious disease
research.
[Back to top]
Aminoglycosidic Aminocyclitol Antibiotics-A Wonder,
But Toxic Drugs: Developments and Clinical Implications
M. Shahid
Aminoglycosides are aminoglycosidic aminocyclitols that contain
amino sugars linked to an aminocyclitol ring by glycosidic
bonds. Although relatively toxic compared with other classes
of antibiotics, they remain primarily useful drugs in the
treatment of infections caused by gram-negative bacteria.
Since the advent of streptomycin by Waksman and co-workers,
a series of milestone compounds like kanamycin, gentamicin,
and tobramycin were introduced for the treatment of gram-negative
bacillary infections. In 1970s, the semisynthetic aminoglycosides
dibekacin, amikacin, and netilmicin demonstrated the possibility
of obtaining compounds active against resistant strains that
had developed resistance mechanisms towards earlier aminoglycosides.
However, since then, the pace of development of new aminoglycosides
has markedly slowed down. This review not only provides the
comprehensive accounts of the developments in aminoglyco-side
antibiotics, but also provides insight about the mechanism
of action and resistance, current efforts to develop aminoglycoside
mimetics that target RNA, and potential strategies to overcome
inactivation of aminoglycosides by aminogly-coside-modifying
enzymes. Some of the interesting clinical implications like
natural aminoglycoside resistances typical of common pathogens,
prediction of responsible aminoglycoside-modifying enzyme
from antibiogram data, and the use of liposomal-encapsulated
aminoglycosides to increase the therapeutic index have also
been discussed.
[Back to top]
Inactivation of Pathogenic Microorganisms by Photodynamic
Techniques: Mechanistic Aspects and Perspective Applications
Giulio Jori and Olimpia Coppellotti
The worldwide rise in antibiotic resistance by microorganisms
has stimulated intensive research toward the development of
alternative therapeutic strategies. Photodynamic therapy (PDT)
is emerging as a promising modality for the treatment of localized
microbial infections. Studies on the relationship between
the chemical structure of photosensitising agents and their
phototoxicity against microbial pathogens led to the identification
of a selected number of compounds with optimal cytocidal effects.
These include phenothiazine, porphyrin and phthalocyanine
derivatives, whose molecule has been engineered to introduce
the following features: (a) presence of cationic moieties,
preferably due to quaternarized amino groups; (b) introduction
of at least one N-alkyl group having a relatively long hydrocarbon
chain; (c) overall amphiphilic character to promote the partitioning
in the plasma membrane.
Studies on cell cultures indicate that PDT is endowed with
favourable properties to act as an antimicrobial modality:
(a) broad spectrum of action, since one irradiation protocol
can be used to obtain the inactivation of different groups
of pathogens, such as Gram-positive and Gram-negative bacteria,
yeasts, mycoplasmas and protozoa in both vegetative and cystic
stages; (b) fast association with microbial cells, which allows
irradiations to be performed after incubation times as short
as 5-10 min., thereby guaranteeing a high selectivity as compared
with host tissues; (d) high photoinactivation efficiency,
since a 5-6 log decrease in microbial population is obtained
by irradiation under mild conditions; (e) photosensitising
activity independent of the antibiotic-resistance spectrum
of the given pathogen; (f) lack of selection of photoresistant
strains upon repeated treatment and minimal risk to induce
the onset of mutagenic processes.
Initial clinical trials involve the treatment of chronic ulcers
and selected oral infections.
[Back to top]
Medicinal Use of Lincosamides and Microbial Resistance
to Them
Tomáš Rezanka, Jaroslav Spížek
and Karel Sigler
Lincomycin and its derivatives are antibiotics exhibiting
biological activity against bacteria, especially Gram-positive
ones, and also protozoans. Lincomycin and its semi-synthetic
chlorinated derivative clindamycin are widely used in clinical
practice. Both antibiotics are bacteriostatic, inhibiting
protein synthesis in sensitive bacteria, and they may even
be bactericidal at higher concentrations that can still be
reached in vivo. Clindamycin is usually more active
than lincomycin in the treatment of bacterial infections,
in particular those caused by anaerobic species; it can also
be used for the treatment of important protozoal diseases,
e.g. malaria, most effectively in combination with other antibiotic
or nonantibiotic antimicrobials (primaquine, fosfidomycin,
benzoyl peroxide). Resistance to lincomycin and clindamycin
may be caused by methylation of 23S ribosomal RNA, modification
of the antibiotics by specific enzymes or active efflux from
the bacterial cell. In addition to the various medicinal applications
and modes of microbial resistance to lincosamides, the review
describes the chemical structures of lincosamide antibiotics
and analytical procedures used for identification, separation
and isolation of these compounds and their metabolites. The
biosynthesis of lincomycin and related compounds and its genetic
control are also briefly discussed.
[Back to top]
Revitalized Strategies Against Multi-Resistant Bacteria:
Antimicrobial Photodynamic Therapy and Bacteriophage Therapy
Tim Maisch
The formation and spread of infections by multi-resistant
bacteria is favoured by the absence of hygienic measures to
prevent the spread in hospital settings as well as the frequent
use of antibiotics. Overall, approximately 20% of Staphylococcus
aureus isolates in Europe are reported as methicillin
resistant and cause serious nosocomial infections. Therefore,
the worldwide rise in antibiotic resistance in clinical practise
has led to the search for alternative methods of selectively
destroying pathogens without harming the host tissue. One
“new” approach to treat microbial infections uses
light in combination with a photosensitizer to induce a phototoxic
reaction by reactive oxygen species similar as in photodynamic
therapy of skin cancer. In particular, different classes of
molecules including porphyrins, phthalocyanines, phenothiazine
and fullerenes have demonstrated antimicrobial efficacy against
a broad spectrum of multi-resistant bacteria upon irradiation
with visible light. Another “new” approach is
called bacteriophage therapy, which involves using phages
or their products as bioactive agents for the prophylaxis
and/or treatment of bacterial infectious diseases. Phages
were used topically, orally or systemically and have demonstrated
efficacy against Gram (-) bacteria, whereas purified phage-encoded
agents are also effective against Gram (+) bacteria.
This review will focus on some aspects of both revitalized
antimicrobial strategies that appear to be especially convenient
for the treatment of infections caused by multi-resistant
bacteria in the future.
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