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Infectious Disorders - Drug Targets
(Formerly 'Current Drug Targets - Infectious Disorders')
ISSN: 1871-5265
Infectious Disorders
– Drug Targets
Volume 7, Number 2, June 2007
Contents
Editorial: Pp.
71-72
Robert C. Goldman and Barbara E. Laughon
The Evolution of Extensively Drug Resistant Tuberculosis
(XDR TB): History, Status and Issues for Global Control
Pp. 73-91
Robert C. Goldman, Kevin V. Plumley and Barbara E. Laughon
[Abstract]
Programs to Facilitate Tuberculosis Drug Discovery:
The Tuberculosis Antimicrobial Acquisition and Coordinating
Facility Pp. 92-104
R. C. Goldman, B.E. Laughon, R. C. Reynolds, J. A. Secrist
III, J. A. Maddry, M.-A. Guié, A. C. Poffenberger,
C. A. Kwong and S. Ananthan
[Abstract]
Challenges Associated with Current and Future TB Treatment
Pp. 105-119
M. Laurenzi, A. Ginsberg and M. Spigelman
[Abstract]
Molecular Approaches to Target Discovery: - Evaluating
Targets for Anti-tuberculosis Drug Discovery Programmes
Pp. 120-126
T. S. Balganesh and B. J. A. Furr
[Abstract]
High Throughput Crystallography of TB Drug Targets
Pp. 127-139
A.C. Murillo, H.Y. Li, T. Alber, E.N. Baker, J.M. Berger,
L.T. Cherney, M.M. Cherney, Yoon Song Cho, D. Eisenberg, C.R.
Garen, C.W. Goulding, L. W. Hung, T.R. Ioerger, W.R. Jacobs,
M.N.G. James, C. Kim, I. Krieger, J.S. Lott, R. Sankaranarayanan,
B.W. Segelke, T.C. Terwilliger, F. Wang, S. Wang and J.C.
Sacchettini
[Abstract]
Drug Targets in Mycobacterial Sulfur Metabolism
Pp. 140-158
Devayani P. Bhave, Wilson B. Muse III and Kate S. Carroll
[Abstract]
Mycobacterium tuberculosis DNA Gyrase as
a Target for Drug Discovery Pp. 159-168
Khisimuzi Mdluli and Zhenkun Ma
[Abstract]
Type II NADH:Menaquinone Oxidoreductase of Mycobacterium
tuberculosis Pp. 169-181
J. S. Teh, T. Yano and H. Rubin
[Abstract]
Targeting the Formation of the Cell Wall Core of M.
tuberculosis Pp. 182-202
Clifton E. Barry, Dean C. Crick and Michael R. McNeil
[Abstract]
Abstracts
[Back to top]
Editorial: Tuberculosis Drugs and
Drug Targets
More than one-third of the global population is infected
with the tuberculosis (TB) and TB remains one of the world’s
leading causes of disease and death. Each year, 8 million
people become ill with TB and 2 million people die from the
disease. In addition, drug resistance in the form of MDR-TB
(strains resistant to isoniazid and rifampicin) and XDR-TB
(strains resistant to isoniazid and rifampicin, and to a fluoroquinolone
and one of the injectable TB drugs [kanamycin, amikacin or
capreomycin]) is making it more difficult to deliver effective
therapy leading to a cure. Although drug discovery for new
antitubercular agents diminished for many years, resurgence
took place over the last several years with support from governments,
research institutes, and non-profit foundations. Today there
is active research in identifying new targets for drug discovery,
validating new targets, and discovering new lead compounds
for drug development. Although there are four new agents undergoing
clinical trials, most are in the early stages and the final
outcome is not yet known. Thus, efforts need to continue,
especially efforts to discover new agents that can dramatically
shorten the time needed in therapy. This special topics issue
of Infectious Disorders – Drug Targets focuses on TB
drugs, drug development and drug targets.
The Evolution of Extensively Drug Resistant Tuberculosis
(XDR-TB): History, Status and Issues for Global Control
(Goldman, Plumley and Laughon): The selection and spread of
multiple drug resistant M. tuberculosis continued
for decades leading to selection and spread of two operationally
distinct forms, multiple drug resistant (MDR-TB) and extensively
drug resistant (XDR-TB). The estimate for MDR-TB and XDR-TB
cases globally for 2005 were 424,000 and 27,000 respectively,
and the situation is worst in areas with high incidences of
HIV infection. This situation was brought to the forefront
when an outbreak of XDR-TB occurred in Tugela Ferry, KwaZulu-Natal,
South Africa, in 2005 and began to spread. The evolution of
XDR-TB is reviewed in terms of its causes, commentary from
the research and lay communities, and future health care needs
to contain the global epidemic.
Programs to Facilitate Tuberculosis Drug Discovery:
The Tuberculosis Antimicrobial Acquisition and Coordinating
Facility (Goldman, Laughon, Reynolds, Secrist III,
Maddry, Poffenberger, Kwong, and Subramaniam): The Tuberculosis
Antimicrobial Acquisition and Coordinating Facility (TAACF)
was founded to make comprehensive testing services available
at no cost to research laboratories with an interest in discovering
new TB drugs. The TAACF is managed and funded by the National
Institute of Allergy and Infectious Diseases (National Institutes
of Health, Bethesda, MD) as a resource to support preclinical
drug discovery and development and consists of a series of
government contracts supporting compound acquisition and storage,
in vitro evaluation of antimycobacterial activity
and cytotoxicity, development of high throughput assays, in
vivo evaluation of toxicity, oral bioavailability and
efficacy in animal models, specialty testing (such as activity
against non-replicating persistent bacteria), and a component
to assist in technology transfer for developing comprehensive
promotional packages and facilitating partnerships with pharmaceutical
companies for drug development.
Challenges Associated with Current and Future TB Treatment
(Laurenzi, Ginsberg and Spigelman): The current and
future status of TB drugs is reviewed in the context of the
emergence of drug resistance and the high incidence of TB-HIV
co-infection. The difficulties in optimizing the use of existing
drugs and challenges for development of novel, improved products
for effectively treating TB are discussed.
Molecular Approaches to Target Discovery: Evaluating
Targets for Antituberculosis Drug Discovery Programmes
(Balganesh and Furr): Issues related to the selection of valid
targets for drug discovery are reviewed, including the issue
of host targeting non-replicating, persistent bacteria. Factors
for use in prioritizing targets are discussed along with the
use of genomic information.
High Throughput Crystallography of TB Drug Targets
(Murillo, Alber, Baker, Berger, Cherney, Cherney, Eisenberg,
Garen, Hung, Ioerger, Jacobs, James, Kim, Kriger, Li, Lott,
Sankaranarayanan, Segelke, Terwilliger, Wang and Sacchettini):
A multi-discipline approach is described for characterizing
new drug targets, including those that are essential for persistent
Mtb is described. Factors used in target prioritization are
reviewed in the context of a structural genomics program.
Drug Targets in Mycobacterial Sulfur Metabolism
(Devayani, Wilson, Muse and Carroll): Survival and the expression
of virulence in many pathogenic bacteria are dependent on
sulfur metabolic pathways. Our current understanding of the
enzymes involved in production of sulfated and reduced sulfur-containing
metabolites in Mycobacteria is reviewed along with
progress in identification of probe for investigating pathway
perturbation. Since microbial sulfur metabolic pathways are
largely absent in humans, these pathways represent unique
targets for therapeutic intervention.
Mycobacterium tuberculosis
DNA gyrase as a Target for Drug Discovery (Mdluli
and Ma): M. tuberculosis contains gyrA and
gyrB (the A and B subunits of DNA gyrase, topoisomerase
II) but appears not to contain topoisomerase IV. Gryase biology
is discussed in the context of the use of current fluoroquinolones
for therapy and the discovery of newer quinolone with improved
activity, especially targeting non-replicating persistent
bacteria.
Type II NADH: Menaquinone Oxidoreductase of Mycobacterium
tuberculosis (Teh, Yano and Rubin): The respiratory
chain in Mtb is reviewed as a possible drug target. Phenothiazines,
which inhibit one of the key enzymes of the respiratory chain,
type II NADH: menaquinone oxidoreductase or NDH-2), are discussed
in the context of the factors relating to inhibition of the
respiratory process in Mtb.
Targeting the Formation of the Cell Wall Core of M.
tuberculosis (Barry, Crick, and McNeil): Synthesis
of the cell integument in Mtb is reviewed in the context of
current drugs that perturb the process and our understanding
of the biochemistry involved. The search for new targets and
lead compounds that inhibit key steps in wall biosynthesis,
specifically synthesis of peptidoglycan, and mycolic acids,
and arabinogalactan polysaccharides, is discussed.
“This preface was written by Dr. Robert C. Goldman and
Dr. Barbara E. Laughon in their capacity as Editors for this
issue of Infectious Disorders - Drug Targets. The views expressed
in this preface and journal do not necessarily represent the
views of the NIH, DHHS, or the United States. The National
Institute of Allergy and Infectious Diseases (NIAID) shall
not accept liability for any statement made that are the Editors
own and not expressly made on behalf of the NIAID by one of
its representatives.”
Robert C. Goldman
Barbara E. Laughon
Editor-in-Chief
Infectious Disorders - Drug Targets
March 2007
[Back to top]
The Evolution of Extensively Drug Resistant Tuberculosis
(XDR TB): History, Status and Issues for Global Control
Robert C. Goldman, Kevin V. Plumley and Barbara E. Laughon
Tuberculosis (TB) is a devastating disease caused by Mycobacterium
tuberculosis that killed an estimated 4000-5000 person
each day during 2005. Although infections with drug sensitive
strains can be effectively cured with a 6 to 9 month regimen
of multiple antibiotics, the inability to deliver and complete
appropriate courses of therapy on a global level has led to
the selection of resistant strains over the past 50 years.
The selection and spread of multiple drug resistant M.
tuberculosis continued for decades leading to two operationally
distinct forms of the disease, multiple drug resistant (MDR-TB)
and extensively drug resistant (XDR-TB). The estimate for
MDR-TB and XDR-TB cases for 2005 were 424,000 and 27,000 respectively,
and the situation is worst in areas with high incidences of
HIV infection. The outcome was predictable based on basic
microbiological principles, and the resultant and future epidemic
effectively modeled mathematically. This situation was brought
to the forefront when an outbreak of XDR-TB occurred in Tugela
Ferry, KwaZulu-Natal, South Africa, in 2005 and began to spread.
Unfortunately, we do not know the true extent of XDR-TB globally.
However, all signs point to an emerging epidemic of TB infections
that will be difficult, if not impossible to cure. A few new
drugs are in clinical trials, but it is too early to know
the final outcome; some may fail, and none will be available
for several years. The situation will continue to worsen unless
more resources are made available to discover and deliver
better treatment options.
[Back to top]
Programs to Facilitate Tuberculosis Drug Discovery:
The Tuberculosis Antimicrobial Acquisition and Coordinating
Facility
R. C. Goldman, B.E. Laughon, R. C. Reynolds, J. A. Secrist
III, J. A. Maddry, M.-A. Guié, A. C. Poffenberger,
C. A. Kwong and S. Ananthan
There is a real need to discover new drugs that are active
on drug-resistant tuberculosis (TB), and for drugs that will
shorten the time of therapy. Large pharmaceutical companies
have traditionally led the quest for discovering and developing
new antiinfective agents but this is not the case when it
comes to diseases like tuberculosis that primarily occur in
resource restricted countries. Throughout the world many research
groups are actively engaged in the scientific discovery of
new TB drugs. Unfortunately, most research laboratories do
not have the necessary safety facilities or resources for
all facets of TB drug discovery. The Tuberculosis Antimicrobial
Acquisition and Coordinating Facility (TAACF) was established
in order to make comprehensive testing services available
at no cost to research laboratories with an interest in discovering
new TB drugs. The TAACF is a consortium of contracts managed
and funded by the National Institute of Allergy and Infectious
Diseases (National Institutes of Health, Bethesda, MD) as
a resource to support preclinical drug discovery and development.
The core of the TAACF is the Southern Research Institute,
Birmingham, AL, which supports compound acquisition, storage,
medicinal chemistry, and high throughput assays. Other collaborating
groups provide biological data on antimycobacterial activity
and cytotoxicity, preliminary in vivo toxicity, oral
bioavailability and efficacy in animal models, specialty testing
(such as activity against non-replicating persistent bacteria),
and assistance in technology transfer for developing comprehensive
promotional packages and facilitating partnerships with pharmaceutical
companies for drug development. The TAACF program and recent
progress that has been publicly disclosed by suppliers is
reviewed. There are many aspects promising of the program
that will not be discussed due to confidentially.
[Back to top]
Challenges Associated with Current and Future TB Treatment
M. Laurenzi, A. Ginsberg and M. Spigelman
Current tuberculosis (TB) treatment is based on a combination
of drugs that were developed mostly in the central decades
of the last century. Cure rates are high for drug sensitive
strains of Mycobacterium tuberculosis (M. tb) when
the recommended complex and lengthy treatment protocols are
adhered to. However the difficulty in correctly prescribing
and adhering to these protocols, the emergence of M. tb
strains resistant to multiple drugs, and drug-drug interactions
that interfere with optimal treatment of HIV and TB co-infected
patients have generated a pressing need for improved TB therapies.
Together with the ominous global burden of TB, these shortcomings
of current treatment have contributed to a renewed interest
in the development of improved drugs and protocols for the
treatment of tuberculosis. This article highlights hurdles
related to the optimized use of existing drugs and challenges
related to the development of novel, improved products, focusing
in particular on aspects inherent in TB drug clinical development.
Concluding comments propose processes for more efficient development
of new TB therapies.
[Back to top]
Molecular Approaches to Target Discovery: - Evaluating
Targets for Anti-tuberculosis Drug Discovery Programmes
T. S. Balganesh and B. J. A. Furr
Selection of appropriate targets for launching antituberculosis
drug discovery programmes is challenging. This challenge is
magnified by the limited repertoire of ‘validated targets’
and the paucity of clinically successful drugs. However, continued
understanding of the biology of the microbe and its interaction
with the host has enabled detailed evaluation of several interesting
pathways and novel targets. The value of a target that is
suitable for antituberculosis drug discovery needs to be defined
not only in the context of its ‘essentiality’
for survival in vitro but also against a variety
of properties relevant to activities in the drug discovery
process, e.g.; selectivity, vulnerability, suitability for
structural studies, ability to monitor inhibition in whole
cells etc. It is also rarely feasible to obtain all the relevant
information on the target prior to the launch of a discovery
programme. Thus, there is a continuous confidence-building
exercise on the validity of a target. Several novel approaches
have enabled exploitation of the mycobacterial genome and
prioritisation of putative targets; the concept of ‘sterilisation’
is now being evaluated not only through the availability of
structurally diverse probe compounds but also by the ability
to characterise metabolic pathways in vivo. The impact
of the current knowledge base on the different facets of ‘target
validation’ relevant to antituberculosis drug discovery
is discussed in this article with emphasis on developing appropriate
matrix systems to prioritise them. The article also discusses
the influence of lead generation approaches with specific
reference to antibacterial drug discovery.
[Back to top]
High Throughput Crystallography of TB Drug Targets
A.C. Murillo, H.Y. Li, T. Alber, E.N. Baker, J.M. Berger,
L.T. Cherney, M.M. Cherney, Yoon Song Cho, D. Eisenberg, C.R.
Garen, C.W. Goulding, L. W. Hung, T.R. Ioerger, W.R. Jacobs,
M.N.G. James, C. Kim, I. Krieger, J.S. Lott, R. Sankaranarayanan,
B.W. Segelke, T.C. Terwilliger, F. Wang, S. Wang and J.C.
Sacchettini
Tuberculosis (TB) infects one-third of the world population.
Despite 50 years of available drug treatments, TB continues
to increase at a significant rate. The failure to control
TB stems in part from the expense of delivering treatment
to infected individuals and from complex treatment regimens.
Incomplete treatment has fueled the emergence of multi-drug
resistant (MDR) strains of Mycobacterium tuberculosis
(Mtb). Reducing non-compliance by reducing the duration
of chemotherapy will have a great impact on TB control. The
development of new drugs that either kill persisting organisms,
inhibit bacilli from entering the persistent phase, or convert
the persistent bacilli into actively growing cells susceptible
to our current drugs will have a positive effect. We are taking
a multi-disciplinary approach that will identify and characterize
new drug targets that are essential for persistent Mtb.
Targets are exposed to a battery of analyses including microarray
experiments, bioinformatics, and genetic techniques to prioritize
potential drug targets from Mtb for structural analysis.
Our core structural genomics pipeline works with the individual
laboratories to produce diffraction quality crystals of targeted
proteins, and structural analysis will be completed by the
individual laboratories. We also have capabilities for functional
analysis and the virtual ligand screening to identify novel
inhibitors for target validation. Our overarching goals are
to increase the knowledge of Mtb pathogenesis using
the TB research community to drive structural genomics, particularly
related to persistence, develop a central repository for TB
research reagents, and discover chemical inhibitors of drug
targets for future development of lead compounds.
[Back to top]
Drug Targets in Mycobacterial Sulfur Metabolism
Devayani P. Bhave, Wilson B. Muse III and Kate S. Carroll
The identification of new antibacterial targets is urgently
needed to address multidrug resistant and latent tuberculosis
infection. Sulfur metabolic pathways are essential for survival
and the expression of virulence in many pathogenic bacteria,
including Mycobacterium tuberculosis. In addition,
microbial sulfur metabolic pathways are largely absent in
humans and therefore, represent unique targets for therapeutic
intervention. In this review, we summarize our current understanding
of the enzymes associated with the production of sulfated
and reduced sulfur-containing metabolites in Mycobacteria.
Small molecule inhibitors of these catalysts represent valuable
chemical tools that can be used to investigate the role of
sulfur metabolism throughout the Mycobacterial lifecycle
and may also represent new leads for drug development. In
this light, we also summarize recent progress in the development
of inhibitors of sulfur metabolism enzymes.
[Back to top]
Mycobacterium tuberculosis DNA Gyrase as
a Target for Drug Discovery
Khisimuzi Mdluli and Zhenkun Ma
Bacterial DNA gyrase is an important target of antibacterial
agents, including fluoroquinolones. In most bacterial species,
fluoroquinolones inhibit DNA gyrase and topoisomerase IV and
cause bacterial cell death. Other naturally occurring bacterial
DNA gyrase inhibitors, such as novobiocin, are also known
to be effective as antibacterial agents. DNA gyrase is an
ATP-dependent enzyme that acts by creating a transient double-stranded
DNA break. It is unique in catalyzing the negative supercoiling
of DNA and is essential for efficient DNA replication, transcription,
and recombination. DNA gyrase is a tetrameric A2B2
protein. The A subunit carries the breakage-reunion active
site, whereas the B subunit promotes ATP hydrolysis. The M.
tuberculosis genome analysis has identified a gyrB-gyrA
contig in which gyrA and gyrB encode the A and
B subunits, respectively. There is no evidence that M.
tuberculosis has homologs of the topoisomerase IV, parC
and parE genes, which are present in most other bacteria.
Newer fluoroquinolones, including moxifloxacin and gatifloxacin,
exhibit potent activity against M. tuberculosis,
and show potential to shorten the duration for TB treatment.
Resistance to fluoroquinolones remains uncommon in clinical
isolates of M. tuberculosis. M. tuberculosis
DNA gyrase is thus a validated target for anti-tubercular
drug discovery. Inhibitors of this enzyme are also active
against non-replicating mycobacteria, which might be important
for the eradication of persistent organisms. A novel inhibitor
of M. tuberculosis DNA gyrase would be effective
against multi-drug resistant (MDR)-TB, and it could also be
effective against fluoroquinolone-resistant M. tuberculosis.
[Back to top]
Type II NADH:Menaquinone Oxidoreductase of Mycobacterium
tuberculosis
J. S. Teh, T. Yano and H. Rubin
Mycobacterium tuberculosis (Mtb) remains the deadliest bacterial
pathogen worldwide, causing an estimated 1.7 million deaths
in 2004 among an infected population of approximately 2 billion
people, according to the World Health Organization (WHO).
Therapeutic options are limited to a few drugs that are becoming
increasingly ineffective. Multidrug-resistant (MDR) Mtb strains
are prevalent globally, fueled by inadequate patient compliance
of drug intake. Recently, a high incidence of extensively
drug-resistant (XDR) strains resistant to all currently used
drugs was reported among patients with the human immunodeficiency
virus (HIV) in KwaZulu Natal, South Africa [1]. The high mortality
rate and short survival time of patients with XDR Mtb was
especially alarming. The emergence of XDR mycobacteria emphasizes
the urgent need for the identification of novel targets and
development of new drugs.
New potential drug targets exist in the Mtb respiratory chain.
Certain classes of drugs have long been shown to exert significant
tuberculocidal activity, such as the phenothiazines [2, 3].
Phenothiazines inhibit one of the key enzymes of the respiratory
chain; type II NADH:menaquinone oxidoreductase or NDH-2 [4].
The effectiveness of this class of drugs against Mtb justifies
further research into the respiratory chain, with the aim
of elucidating its physiologic roles in in vitro
and in vivo survival, and discovering new (sub)classes
of drugs that can safely serve as inhibitors for clinical
use. In this chapter, we critically review the recent advances
in this field, with particular emphasis on NDH-2, and underscore
the kinds of research further needed for drug development.
[Back to top]
Targeting the Formation of the Cell Wall Core of M.
tuberculosis
Clifton E. Barry, Dean C. Crick and Michael R. McNeil
Mycobacteria have a unique cell wall, which is rich in drug
targets. The cell wall core consists of a peptidoglycan layer,
a mycolic acid layer, and an arabinogalactan polysaccharide
connecting them. The detailed structure of the cell wall core
is largely, although not completely, understood and will be
presented. The biosynthetic pathways of all three components
reveal significant drug targets that are the basis of present
drugs and/or have potential for new drugs. These pathways
will be reviewed and include enzymes involved in polyisoprene
biosynthesis, soluble arabinogalactan precursor production,
arabinogalactan polymerization, fatty acid synthesis, mycolate
maturation, and soluble peptidoglycan precursor formation.
Information relevant to targeting all these enzymes will be
presented in tabular form. Selected enzymes will then be discussed
in more detail. It is thus hoped this chapter will aid in
the selection of targets for new drugs to combat tuberculosis.
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