Hyungjin Eoh

PIBBS MENTOR

Assistant Professor

Molecular Microbiology and Immunology
Keck School of Medicine

Research Topics

  • Discovery of novel anti-tuberculosis drugs using metabolomics

Research Overview

Research Overview

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), faces a particularly
unique challenge in that it resides within human. Infecting humans, Mtb dwells chiefly amidst a localized
collection of pro-inflammatory immune cells that can form a granuloma. Under such circumstances, Mtb
encounters multiple adverse conditions as host derived innate immunity which interferes with Mtb
normal pathogenicity. Mtb, however, evolutionarily achieves the capacity to enter in a state of slowed
or arrested replication. Indeed, the majority of TB patients harbor this non-replicating (NR) form of Mtb
that are asymptomatic, tolerant to most existing TB drugs and poised to transmit to a new host.
Unfortunately, we are only beginning to exploit the strategies Mtb uses to sense environmental
information to initiate responses, accordingly. My laboratory thus will be focused on expanding our
knowledge of the specific metabolic programs used by Mtb to complete its lifecycle as a source of drug
targets.

Metabolic activities essential for transition between replicating and non-replicating forms of Mtb.
Mtb spends the majority of its lifetime in a state of slowed or arrested replication while
remaining poised to reenter cell cycle in response to host immunity. Within such environments, Mtb
encounters multiple growth non-permissive conditions that include the depletion of essential nutrients
or biochemical components (carbon, nitrogen, phosphorus, magnesium, oxygen, and iron), an acidic pH
and generation of reactive oxygen species, reactive nitrogen species and antimicrobials. Remarkably, the
capacity of transitioning into a viable NR Mtb state is evolutionarily achieved by remodeling of its
multilayered regulatory metabolic networks. To address this,

• First, my laboratory will assess the metabolic remodeling associated with transition into NR latency
as induced by host-specific stresses presented either in isolation or combination. To this aim, I will
use isotopic tracing Liquid Chromatography Mass Spectrometry (LC-MS) metabolomics.

• Second, Mtb harbors multilayered regulatory machineries, transcriptional and metabolic. Dormancy
survival regulon (Dos regulon) is one of the best studied vanguards of the transcriptional response
to low oxygen. Thus, LC-MS based metabolomics will be applied to Dos regulon deficiency Mtb to
provide integrated views of the transcriptional and metabolic regulatory networks.

• Third, adaptive regulatory networks during transition states require biochemical/molecular bases
which are still undefined. My laboratory will, thus, reveal the regulatory mechanisms by defining; (i)
post-translational modification of target enzymes, (ii) allosteric regulation, and (iii) conditiondependent
switched interactive partners.

 Products of various stages of Mtb interactive with host innate immune system

Host immune system acts as an internal shield against invading Mtb. Thus, intervention in the
host cell responses against Mtb infection should promise to expand therapeutic option.

• Invading Mtb interacts with host cells through either physical contact or indirect modulation of
signaling cascades with secreted mediators. My laboratory will thus seek to establish the repertoires
of key candidates out of cell surface by using LC-MS based glycolipidomics and exometabolomics.

Based upon the answer for open questions; the studies will lead to a better understanding of Mtb
physio-chemistry, metabolism, and pathogenesis adaptive to environmental changes including
antibiotics treatment. This could facilitate to the development of conceptually novel strategies develop
new drugs to improve current TB control.