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Ann Biol Sci, 2017
ISSN: 2348-1927
August 23-24, 2017 | Toronto, Canada
Annual Conference on
MICROBIAL PATHOGENESIS, INFECTIOUS DISEASE,
ANTIMICROBIALS AND DRUG RESISTANCE
Tuberculosis is a dreadful disease caused by a successful
human pathogen Mycobacterium tuberculosis (M.
tb). Strict compliance to long chemotherapy, lack of
diagnostics and vaccines has led to emergence of MDR
(multi drug-resistant) and XDR (extensively drug-resistant)
strains. Therefore, better understanding of metabolic
relationship and interactions among host and pathogen are
of fundamental importance for better design of effective
vaccine and drug therapies. Availability of essential nutrients,
cofactors, and metabolites are of prime importance for
successful survival and proliferation of any pathogen. Many
pathogens like Legionella, Coxiella, Francisella, Salmonella
and Listeria have acquired the ways to sustain them by
acquiring nutrients, cofactors and essential metabolites from
the host. However M. tuberculosis lives autonomic life style
and is equipped with its own biosynthetic pathways for most
of the nutrients, which along with being boon also makes
M. tb more vulnerable. Most of the auxotrophs of M. tb
are not proliferate but they survive and persist. Here, using
genetic approach, we have discovered novel bactericidal
auxotrophies, which rapidly kill M. tb in vitro as well as in
vivo without the appearance of any suppressor mutants.
M. tb auxotrophs in these pathways got rapidly killed in
immunocompetent, immunodeficient mouse models and
in macrophages, despite recruitment of macrophage amino
acid transporter on phagosomes. Time course metabolomic
and transcriptomic studies on starved cells showed
multifactorial mechanism of death involving perturbances in
envelope integrity and redox imbalance leading to oxidative
stress followed by rapid cell death. Furthermost excitingly,
screening fragment library we have obtained fragment
inhibitors which cause allosteric inhibition of enzymes in
the pathway. Thus, our findings identify a novel attractive
target for antimycobacterial therapy and may be for other
pathogens also.
e:
Bactericidal auxotrophy as new drug target space to eliminate persistent human pathogen
Mycobacterium tuberculosis
Sangeeta Tiwari
Adjunct Assistant Professor,USA
Arch Clin Microbiol, 8:5
DOI: 10.4172/1989-8436-C1-003