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Infectious Disorders - Drug Targets
(Formerly 'Current Drug Targets - Infectious Disorders')
ISSN: 1871-5265
Infectious Disorders
– Drug Targets
Volume 6, Number 2, June 2006
Contents
Efflux Pumps in Drug Resistance of Candida
Pp. 69-83
R. Prasad, N. A. Gaur, M. Gaur and S. S. Komath
[Abstract]
Phospho-MurNAc-Pentapeptide Translocase (MraY) as
a Target for Antibacterial Agents and Antibacterial Proteins
Pp. 85-106
Timothy D.H. Bugg, Adrian J. Lloyd and David I. Roper
[Abstract]
Recent Developments in Drug Targets and Delivery of
Anti-HIV Drugs Pp. 107-119
Noha N. Salama, Aaron Endsley and Rodney J.Y. Ho
[Abstract]
Targets and Tools: Recent Advances in the Development
of Anti HCV Nucleic Acids Pp. 121-145
C. Romero-López, F. J. Sánchez-Luque and A.
Berzal-Herranz
[Abstract]
Combating Vancomycin Resistance in Bacteria:
Targeting the D ala-D-ala Dipeptidase VanX
Pp. 147-158
Michael W. Crowder
[Abstract]
New Trends in Development of Antimycobacterial Compounds
Pp. 159-172
M. Biava, G.C. Porretta, D. Deidda and R. Pompei
[Abstract]
Novel Approaches to Antimalarial Drug Discovery
Pp. 173-204
Christophe Biot and Kelly Chibale
[Abstract]
Abstracts
[Back to top]
Efflux Pumps in Drug Resistance of Candida
R. Prasad, N. A. Gaur, M. Gaur and S. S. Komath
The incidences of human pathogenic yeast Candida
albicans and its related species acquiring resistance
to antifungals have increased considerably, which poses serious
problems towards its successful chemotherapy. The resistance
of these pathogenic fungi is not restricted to the commonly
used triazole compounds but is even encountered, though not
often, with polyene derivatives as well. The efflux pump proteins
belonging to ABC (ATP Binding Cassette) and MFS (Major Facilitators)
super family are the most prominent contributors of multidrug
resistance (MDR) in yeasts. The abundance of the drug transporters
and their wider specificity suggest that these transporters
may not be exclusively drug exporters in yeasts and may have
other cellular functions. In this article we focus on some
of the recent advances on the structure and function, evolution
and transcriptional control of drug efflux proteins of Candida.
A short discussion on the physiological relevance of drug
transporters is also included.
[Back to top]
Phospho-MurNAc-Pentapeptide Translocase (MraY) as
a Target for Antibacterial Agents and Antibacterial Proteins
Timothy D.H. Bugg, Adrian J. Lloyd and David I. Roper
Phospho-MurNAc-pentapeptide translocase (MraY, translocase
I) catalyses the first step of the lipid-linked cycle of reactions
of bacterial peptidoglycan biosynthesis. MraY is the target
for five families of nucleoside antibacterial natural products:
the tunicamycins, the mureidomycins (also pacidamycins, napsamycins),
the liposidomycins, the muraymycins, and the capuramycins.
Recent structure-activity studies on these families have led
to the identification of active pharmacophores, and insight
into their mechanisms of action. This step of peptidoglycan
biosynthesis is also the target for the bacteriolytic E protein
from bacteriophage ΦX174,
and for cyclic peptides of the amphomycin family which complex
the undecaprenyl phosphate co-substrate.
The mechanisms of enzyme inhibition by these agents are discussed,
and the state of knowledge regarding the transmembrane structure,
active site, and catalytic mechanism of MraY. The availability
of high throughput assays and prospects of MraY as an antibacterial
target are also discussed.
[Back to top]
Recent Developments in Drug Targets and Delivery of
Anti-HIV Drugs
Noha N. Salama, Aaron Endsley and Rodney J.Y. Ho
With almost 40 million people infected with human immunodeficiency
virus (HIV), it is one of the most devastating diseases with
no cure in sight. Over the past two decades, significant progress
has been made to identify and validate drug targets for HIV.
However, most of the 20 FDA approved drugs are targeted to
two enzymes; reverse transcriptase and protease. Other drug
targets derived from HIV and host factors are being validated,
and novel compounds are being developed to overcome drug resistance.
Recent data indicate that low and residual virus found in
tissues of the lymphoid and central nervous system (CNS) is
likely due to insufficient drug levels. Thus, improvement
in the delivery of anti-HIV drugs to these tissues with limited
drug penetration or accumulation, is equally important to
maximally suppress viral replication. Novel lipid associated
drugs (i.e. indinavir) targeted to the lymphoid tissue have
been shown to overcome limited drug exposure in the lymph
nodes and to further reduce residual virus in tissue. This
review discusses viral and cellular targets that could interrupt
viral replication, as well as novel and proven strategies
to enhance the delivery of anti-HIV drugs to the lymphoid,
CNS, and cells where low viral replication and limited drug
levels exist.
[Back to top]
Targets and Tools: Recent Advances in the Development
of Anti HCV Nucleic Acids
C. Romero-López, F. J. Sánchez-Luque and A.
Berzal-Herranz
Hepatitis C virus (HCV), the major etiological agent of transfusion-associated
non-A, non-B hepatitis, is a severe health problem affecting
up to 3% of the world population. Since its identification
in 1989, enormous efforts have been made to characterize the
viral cycle. However, many details regarding the virus’
penetration of hepatocytes, its replication and translation,
and the assembling of virions remain unknown, mostly because
of a lack of an efficient culture system. This has also hampered
the development of fully effective antiviral drugs. Current
treatments based on the combination of interferon and ribavirin
trigger a sustained virological response in only 40% of infected
individuals, thus the development of alternative therapeutic
strategies is a major research goal. Nucleic acid based therapeutic
agents may be of some potential in hepatitis C treatment.
In recent years, much effort has gone into the improvement
of DNA and RNA molecules as specific gene silencing tools.
This review summarizes the state of the art in the development
of new HCV therapies, paying special attention to those involving
antisense oligonucleotides, aptamers, ribozymes, decoys and
siRNA inhibitors. The identification of potential viral targets
is also discussed.
[Back to top]
Combating Vancomycin Resistance in Bacteria: Targeting
the D ala-D-ala Dipeptidase VanX
Michael W. Crowder
In the past 20 years, vancomycin and other glycopeptide
antibiotics have been administered to patients with Streptococcal
and Staphylococcal infections that were resistant
to all other antibiotics or to patients who were allergic
to penicillins and cephalosporins. After extensive use of
vancomycin and other glycopeptide antibiotics in humans, several
strains of Enterococcus have developed high-level
vancomycin resistance (collectively called VRE, vancomycin-resistant
Enterococcus), and this resistance phenotype has
spread to other organisms. The spread of vancomycin resistance
to other pathogens and, potentially, to bacterial strains
on the CDC's bioterrorism watch list is a major biomedical
concern. Bacteria most often become resistant to vancomycin
by acquiring a transposon containing genes that encode for
a number of proteins, five of which are essential for the
high-level resistance phenotype. The five essential gene products
are called VanR, VanS, VanH, VanA, and VanX. Previous studies
have shown that the inactivation of VanX results in an organism
that is sensitive to vancomycin and that VanX is an excellent
inhibitor target. In this review the known inhibitors and
structural and mechanistic properties of VanX will be discussed.
These data will be used to offer suggestions for novel, rationally-designed
or –redesigned inhibitors, which could potentially be
used in combination with existing glycopeptide antibiotics
as a treatment for vancomycin-resistant bacterial infections.
[Back to top]
New Trends in Development of Antimycobacterial Compounds
M. Biava, G.C. Porretta, D. Deidda and R. Pompei
The resurgence of tuberculosis and the surge of multidrug-resistant
clinical isolates of Mycobacterium tuberculosis
have reaffirmed tuberculosis as a primary public health concern.
In this review we describe some new findings on the pharmacological
status of fluoroquinolones derivatives (Gatifloxacin, Moxifloxacin
and Sitafloxacin), new macrolides (Clarithromycin, Azithromycin
and Roxithromycin), new rifamycin derivatives (Rifapentin,
Rifabutin and Rifalazil) and new oxazolidinones (Linezolid
and PNU 100480). We describe also other type of agents that
are being developed as antimycobacterial drugs. Some of these
are under clinical investigation, while others are considered
to be promising candidates for future development. Among them,
nitroimidazopyrans, new ketolides, Isoxyl (ISO), pyrroles
derived from BM 212, Mefloquine and Diarylquinoline
R207910 are discussed. We also describe the mechanism of drug
resistance in mycobacteria, as well as new potential targets.
[Back to top]
Novel Approaches to Antimalarial Drug Discovery
Christophe Biot and Kelly Chibale
Major advances in our understanding of malaria parasite biology
have been made. Coupled with the completion of the malaria
genome, this has presented exciting opportunities for target-based
antimalarial drug discovery. However, the unraveling of more
validated biological targets will not necessarily translate
into the identification of new chemical entities that are
effective against drug resistant parasites in the long term.
As history has already shown, development of antiplasmodial
agents aimed at a single parasite target or specialized process
has failed to stem the tide of drug resistance. This review
highlights recent starting points and/or approaches to antimalarial
drug discovery with particular emphasis on innovative efforts,
which are not necessarily based on the identification of new
drug targets and attendant inhibitor design. Approaches covered
include utilization of validated chemical scaffolds, bioprecursor
and carrier prodrugs, double drug development and/or multi-therapeutic
strategies, use of metallocenic scaffolds, the medicinal chemistry
of antimalarial natural products and in silico drug
design.
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