Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 7, Number 5, 2007
Contents
Drug-Resistant Tuberculosis - A Challenge
in Chemotherapy
Guest Editor: Iwao Ojima
Editorial Pp. 457
Biographical
Sketches of Authors Pp. 459-461
New Tuberculosis Drugs in Development Pp.
463-473
Barbara E. Laughon
[Abstract]
The Cell-Wall Core of Mycobacterium tuberculosis
in the Context of Drug Discovery Pp. 475-488
Patrick J. Brennan and Dean C. Crick
[Abstract]
Development of Modern InhA Inhibitors to Combat Drug
Resistant Strains of Mycobacterium tuberculosis
Pp. 489-498
Peter J. Tonge, Caroline Kisker and Richard A. Slayden
[Abstract]
Screening for Novel Antituberculosis Agents that are
Effective Against Multidrug Resistant Tuberculosis
Pp. 499-507
Makoto Matsumoto, Hiroyuki Hashizume, Hidetsugu Tsubouchi,
Hirofumi Sasaki, Motohiro Itotani, Hideaki Kuroda, Tatsuo
Tomishige, Masanori Kawasaki and Makoto Komatsu
[Abstract]
Nitrofurans as Novel Anti-tuberculosis Agents: Identification,
Development and Evaluation Pp. 509-526
Rajendra P. Tangallapally, Raghunandan Yendapally, AnTawan
J. Daniels, Robin E.B. Lee and Richard E. Lee
[Abstract]
FtsZ: A Novel Target for Tuberculosis Drug Discovery
Pp. 527-543
Qing Huang, Peter J. Tonge, Richard A. Slayden, Teruo
Kirikae and Iwao Ojima
[Abstract]
Abstracts
[Back to top]
Editorial
In 1993 the World Health Organization declared tuberculosis
a global emergency. Currently, it is estimated that one-third
of the World’s population are infected with Mycobacterium
tuberculosis, the organism that causes TB, and that over
two million people die each year from this disease. While
5-10% of those infected will develop active TB infections,
this percentage rises dramatically in patients with HIV/AIDS.
Indeed, TB is a major opportunistic disease in individuals
with HIV/AIDS, accounting for 11% of the AIDS-related deaths
worldwide each year. Our ability to combat the spread of TB
is hindered by poor patient compliance, the accompanying increase
in multi-drug resistant TB strains (MDR-TB) and the strong
link between TB and HIV/AIDS. In industrialized countries
TB treatment costs around US $2,000 per patient, but rises
more than 100-fold to up to US $250,000 per patient with MDR-TB.
Chemotherapeutics that are active against MDR-TB would therefore
be of tremendous benefit and desperately needed now. These
compounds would be expected to have unique mechanisms of action,
so that mechanisms of resistance as a result of current drug
use would not be expected to impact the mode of action. Consequently,
new TB chemotherapeutics are needed that (1) improve compliance
by either shortening the total duration of treatment or increasing
the time between treatment intervals or both, (2) improve
efficacy against MDR strains, and (3) target metabolically
altered bacterial populations such as latent TB infections.
The Guest Editor organized a symposium on “Drug-Resistant
Tuberculosis --- Challenge in Chemotherapy” at the American
Chemical Society National Meeting, San Diego, in March 2005,
on behalf of the ACS Medicinal Chemistry Division. This symposium
summarized the current status and ongoing endeavors in the
anti-TB chemotherapeutics research to promote the recognition
of this serious problem and stimulate the interest of the
medicinal chemist community. Due to the small profit making
nature of the traditional anti-TB drugs, major pharmaceutical
industries are not working on the anti-TB chemotherapy and
chemotherapeutics at present. However, this unfortunate situation
should be changed to prevent the outbreak of formidable drug-resistant
TB in advanced countries. Following up this ACS Symposium,
the Guest Editor assembled leading scientists relevant to
drug discovery and medicinal chemistry of new generation anti-TB
agents and organized this special issue of the Current
Topics in Medicinal Chemistry. This special issue includes
a very informative overview by Dr. Barbara Laughon, NIAID,
NIH, followed by five articles, representing different approaches
to this challenging problem. The Guest Editor would like to
thank all authors for their excellent contributions to this
special issue and sincerely hopes that this special issue
attracts shear interests of medicinal chemists in academia
and industry to join the worldwide endeavor to combat against
drug-resistant TB.
Iwao Ojima
Institute of Chemical Biology & Drug Discovery
and Department of Chemistry
State University of New York at Stony Brook
Stony Brook
NY 11794-3400
USA
[Back to top]
New Tuberculosis Drugs in Development
Barbara E. Laughon
Over the past 50 years, no new drug classes have been introduced
to treat tuberculosis. Tuberculosis (TB) kills nearly two
million people a year mainly in the poorest communities in
the developing world. It afflicts millions more. About one
third of the world’s population is silently infected
with TB that may erupt into disease with increased age or
suppression of the immune system. Nearly nine million new
active cases develop every year. The World Health Organization
(WHO) declared the disease a global emergency as long ago
as 1993. Although huge efforts in public health control have
reduced the disease burden within most established market
economies, in Africa and Asia the epidemic continues to accelerate,
particularly fueled by the HIV epidemic. Furthermore, resistance
to the standard drugs isoniazid and rifampicin is increasing
worldwide. Since the 1990s, mycobacteria have emerged with
resistance patterns rendering all currently available antibiotics
ineffectual. The pharmaceutical industry has mostly abandoned
TB drug development due to perceived non-profitable consumer
market and the diminishing number of companies engaged in
anti-infective research. The public sector and infectious
disease researchers have responded to advance fundamental
science and to create new chemical entities as early drug
candidates. With support from research funding agencies, philanthropic
donors, and the STOP-TB Partnership, new chemical tools and
new approaches to effectively implement TB control programs
are evolving. Advanced preclinical development and strategies
for Phase III clinical trials remain gap areas that will require
additional engagement from all sectors.
[Back to top]
The Cell-Wall Core of Mycobacterium tuberculosis
in the Context of Drug Discovery
Patrick J. Brennan and Dean C. Crick
Present-day understanding of the architecture of the entire
cell-wall of Mycobacterium tuberculosis amounts to
a “core" template comprised of peptidoglycan with
phosphodiester linkage, via a linker disaccharide, to a linear
D-galactofuran, to which, in turn, are attached several strands
of a highly branched D-arabinofuran. The cell-wall mycolic
acids are linked via an ester to the majority of the non-reducing
termini of the D-arabinan. The mycolic acids are oriented
perpendicular to the plane of the membrane and provide a truly
special lipid barrier responsible for many of the physiological
and disease-inducing aspects of M. tuberculosis.
Intercalated within this environment are the phthiocerol dimycocerosates,
cord factor or dimycolyltrehalose, sulfolipids, phosphatidylinositol
mannosides and the related lipomannan and lipoarabinomannan,
etc., agents responsible for much of the pathogenesis
of tuberculosis. Interest in the biosynthesis of the cell-wall
core, regarded, unlike the ancillary lipids, as essential
to bacterial viability and integrity, is now driven by the
pressing need for alternative drugs to counteract drug-resistant
tuberculosis. In a manner analogous to the roles of lipid
I and II in peptidglycan formation, synthesis of the entire
arabinogalactan is initiated by transferring activated sugars
to decaprenyl phosphate, giving rise to the linker disaccharide,
followed by stepwise elongation of the galactan, and the arabinan,
apparently one sugar at a time. The genetics and enzymology
of these polymerization events have not been well defined,
nor have the final steps, namely the attachment of mycolic
acids and ligation to peptidoglycan. However, what is known
of the earlier events in cell-wall core synthesis has attracted
interest in terms of new anti tuberculosis drug development.
[Back to top]
Development of Modern InhA Inhibitors to Combat Drug
Resistant Strains of Mycobacterium tuberculosis
Peter J. Tonge, Caroline Kisker and Richard A. Slayden
Strategies for the development of novel tuberculosis chemotherapeutics
against existing drug resistant strains involve the identification
and inhibition of novel drug targets as well as the design
and synthesis of compounds against historical targets. InhA,
the enoyl reductase from the mycobacterial type II fatty acid
biosynthesis pathway, is a target of the frontline chemotherapeutic,
isoniazid (INH). Importantly, the majority of INH-resistant
clinical isolates arise from mutations in KatG, the enzyme
responsible for activating isoniazid, into its active form.
Thus compounds that inhibit InhA without first requiring KatG
activation will be active against the majority of INH resistant
strains of Mycobacterium tuberculosis. This review
describes the role of InhA in cell wall biosynthesis and recent
progress in the development of novel diphenyl ether-based
InhA inhibitors that have activity against both sensitive
and drug resistant strains of M. tuberculosis.
[Back to top]
Screening for Novel Antituberculosis Agents that are
Effective Against Multidrug Resistant Tuberculosis
Makoto Matsumoto, Hiroyuki Hashizume, Hidetsugu Tsubouchi,
Hirofumi Sasaki, Motohiro Itotani, Hideaki Kuroda, Tatsuo
Tomishige, Masanori Kawasaki and Makoto Komatsu
The challenges in preventing and controlling tuberculosis
are further complicated by the deadly rise of multi-drug-resistant
tuberculosis (MDR-TB). Recognizing the seriousness of the
situation, we initiated a program to screen new agents that
would satisfy these unmet needs and have a favorable safety
profile. Mycobacteria are well known for their lipid-rich
properties. In Mycobacterium tuberculosis, mycolic
acid in particular has been established the wall component
related to the pathogenesis in the host. There are approximately
250 identified genes related to biosynthesis of the lipid
turnover that contain InhA, the main target of isoniazid.
Thus, the logical approach for developing a chemotherapy agent
against tubercle bacilli included screening compounds that
could inhibit the biosyntheses of mycolic acid and that had
a novel chemical structure to ensure improved efficacy against
MDR-TB. Some of the screening systems established for those
purposes and some of the candidates are outlined.
[Back to top]
Nitrofurans as Novel Anti-tuberculosis Agents: Identification,
Development and Evaluation
Rajendra P. Tangallapally, Raghunandan Yendapally, AnTawan
J. Daniels, Robin E.B. Lee and Richard E. Lee
During a search for new anti-tuberculosis agents, a screen
of a commercially available library provided a hit nitrofuranyl
amide. This hit was selected for further development due to
its potential as an anti-tuberculosis agent with a novel mechanism
of action, and its potential for activity against both actively
growing and latent bacteria. This review covers the optimization
of this lead and the strategies applied for developing this
series into anti-tuberculosis agents. To optimize the hit,
a series of libraries were synthesized, producing several
compounds that showed increased anti-tuberculosis activity
along with a strong structure activity relationship. The most
active compounds from the first optimization series showed
good in vitro anti-tuberculosis activity and limited
in vivo efficacy, but their application was restricted
due to solubility problems. Therefore, a second generation
optimization library was designed and synthesized in order
to increase bioavailability and solubility while maintaining
good anti-tuberculosis activity. Hydrophilic cyclic secondary
amines were substituted to the core scaffold and a benzyl
piperazine substitution was found to be most effective in
achieving improved solubility and potent anti-tuberculosis
activity. However, bioactivity studies of these 2nd generation
leads showed that the in vivo anti-tuberculosis activity
of these compounds was limited due to rapid metabolism. Consequently,
a 3rd generation of compounds was designed and synthesized
in which potential sites of metabolism were blocked.
[Back to top]
FtsZ: A Novel Target for Tuberculosis Drug Discovery
Qing Huang, Peter J. Tonge, Richard A. Slayden, Teruo
Kirikae and Iwao Ojima
The emergence of multi-drug resistant Mycobacterium tuberculosis
(Mtb) strains has made many of the currently available anti-TB
drugs ineffective. Accordingly there is a pressing need to
identify new drug targets. FtsZ, a bacterial tubulin homologue,
is an essential cell division protein that polymerizes in
a GTP-dependent manner, forming a highly dynamic cytokinetic
ring, designated as the Z ring, at the septum site. Following
recruitment of other cell division proteins, the Z ring contracts,
resulting in closure of the septum and then formation of two
daughter cells. Since inactivation of FtsZ or alteration of
FtsZ assembly results in the inhibition of Z ring and septum
formation, FtsZ is a very promising target for new antimicrobial
drug development. This review describes the function and dynamic
behaviors of FtsZ, its homology to tubulin, and recent development
of FtsZ inhibitors as potential anti-TB agents.
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