1. AJBB
Journal Name, 2012, *, **-**
ISSN: 1553-3468
©2012 Science Publication
doi:10.3844/ajbb.2012.***** Published Online *** 2012 (http://www.thescipub.com/journal.toc)
MTAN: A CRITICAL TARGET FOR ANTI QUORUM
SENSING ATNTIBIOTICS
Cindy Chen1,4
, Jake Yu2,4
, Shanzhi Wang3,*
, Fourth Author1
1
Bronx High School of Science Bronx, US;
2
Montgomery High School, Skillman, US.
3
Biochemistry Department, Albert Einstein College of Medicine, Bronx, US
Email: shanzhi.wang@einstein.yu.edu
4
Contributed equally to the manuscript and listed alphabetically
Received Month Day, Year; Revised xxxx; Accepted xxxx
ABSTRACT
This review details the development and impact of drug resistant bacterial strains. Their rapid increase has
prompted research into novel treatment methods that will compromise bacteria without killing them. One
such method targets bacteria’s intercommunication process known as quorum sensing. Bacteria release
signaling molecules called autoinducers. Once the autoinducers reach a critical level, or a quorum, all
neighboring bacteria simultaneously switch gene expression and act in unison. This review shows that the
enzyme 5' –Methylthioadelynosine/ S-adenosylhomocysteine nucleosidase (MTAN) is vital for autoinducer
production. In addition, a recent study proposed a new menaquonone pathway in pathogenic bacteria H.
pylori and C. jejuni in which MTAN plays a vital role. Thus, MTAN is a critical target for antibiotic drug
design. Future studies will focus on how inhibition of MTAN will affect bacteria toxicity. This review
furthers our understanding of the inner workings of bacterial infections.
Keywords: MTAN, Quorum sensing, autoinducers, drug resistance, menaquonone
1

2. AJBB
Journal Name, 2012, *, **-**
ISSN: 1553-3468
©2012 Science Publication
doi:10.3844/ajbb.2012.***** Published Online *** 2012 (http://www.thescipub.com/journal.toc)
1. INTRODUCTION
Antibiotic resistant bacteria are a pressing problem
across the world. Many disease causing bacteria such as
Staphylococcus aureus, Mycobacterium tuberculosis,
Escherichia coli, Vibrio cholera, Pseudomonas
aeruginosa, and Streptococcus pneumonia have
developed resistance against current antibiotics. To fight
these ‘superbacteria’, current research focuses on novel
antibiotics that limit bacteria’s toxicity without killing it,
thereby reducing the chance of developing resistance.
Disrupting quorum sensing to prevent biofilm formation
and release of pathogenic factors could be a viable
strategy. The enzyme MTAN plays a vital role in
quorum sensing pathways and thus is an important target
for antibiotic drug design.
2. Antibiotic Resistant Strains
2.1. Staphylococcus aurea
Since the discovery of antibiotics, antibiotic resistant
strains have significantly increased and become a major
threat in post operative care departments. Each year
approximately two million hospitalizations result in
nosocomial infections. A study in a large teaching
hospital showed that illness due to nosocomial
bacteremia increased intensive care unit stay by 8 days,
hospital stay by 14 days, and the death rate by 35%
among critically ill patients.1
The major cause of death in
hospitals is antibiotic resistant microorganisms in post-
operative care such as Staphylococcus aureus.
Staphylococcus aureus causes a number of diseases as a
result of infection of tissues in the body. Staphylococcal
sepsis is the leading cause of shock and circulatory
collapse. If left untreated, the mortality rate of S. aureus
sepsis is higher than 80%2
. When treated with β-lactam
antibiotics, which have high efficacy against S. aureus,
the mortality rate is still between 20% and 40%.
Recently, S. aureus has developed strains that are
resistant to the drugs used to treat the bacterium. These
drug resistant strains of S. aureus are called Methicillin-
resistant Staphylococcus aureus (MRSA). MRSA usually
targets immunocompromised patients, in which the body
cannot overcome and kill the strong bacteria colonies.
19,000 hospitalized American patients die from MRSA
infections annually; this approaches the number of deaths
due to AIDS, tuberculosis, and viral hepatitis combined .
From 1994 to 2004, there was a 300% increase5
of
staphylococcus infections caused by MRSA. MRSA is
now endemic and epidemic in many hospitals,
comprising nearly 30% of all S. aureus infections6
.
2.2. Mycobacterium tuberculosis
Tuberculosis is a highly contagious airborne disease
caused by Mycobacterium tuberculosis. If left untreated,
a person with active TB will infect between 10 and 15
people per year. In 2010, it was estimated that 8.8
million people were infected and 1.1 million people died
from TB7
. TB is resistant to almost any single drug
treatment. TB is currently treated with a combination of
three or four antibiotics with a treating period of six to
nine months. However, two new strains of Tuberculosis,
called MDR-TB (multi drug resistant) and XDR-TB
(extensively drug resistant) have developed. People
infected with these strains have a high fidelity rate in
spite of prompt antibiotic treatment.
2.3. Escherichia coli
Escherichia coli is the most common bacterium that
causes sepsis. This bacterium infects approximately
73,000 people in the United States every year 8
. Around
500 people in the United States die every year due to E.
coli related diseases. E. coli has developed strains that
are resistant to penicillin and cephalosporin 9
, drugs that
are currently used to treat E. coli diseases.
2.4. Vibrio cholera
Cholera is an infectious disease of the intestine caused by
Vibrio cholera. Every year, approximately three to five
million people are infected by cholera, and 100,000 to
120,000 die from cholera10
. The death rate due to cholera
is about 1%, but if untreated, the mortality rate grows to
60% on average11
. Doxycycline is one of the main
antibiotics used to treat cholera. However, strains of V.
cholera have become drug resistant to these antibiotics.
In 2009 50% of isolated strains of V. cholerae were
tetracycline resistant 12
.
2.5. Pseudomonas aeruginosa
Pseudomonas aeruginosa is a nosocomial pathogen that
causes septic shock and pneumonia. The mortality rate in
patients with septic shock is approximately 40% 13
.
Pneumonia is one of the most common fatal nosocomial
infections, leading to a yearly mortality rate of 33%14
. P.
aeruginosa infections are commonly treated with β
-lactam antibiotics, such as first generation penicillin.
However, strains of P. aeruginosa quickly developed
resistance to these drugs, prompting newer generation
penicillin antibiotics such as Piperacillin sodium. The
novel antibiotics took decades to produce, yet P.
aeruginosa developed resistance in a matter of months.
1

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2.6. Streptococcus pneumoniae
Streptococcus pneumoniae is a bacterium that is the most
common cause of otitis media, sepsis, pneumonia, and
meningitis. Approximately 500,000 cases of pneumonia,
55,000 cases of bacteremia, and 6,000 cases of
meningitis are caused by S. pneumoniae infections
annually in the United States15
.(source doesn’t check) In
2000, S. pneumoniae infections caused 6 million cases of
otitis media, 100,000-135,000 hospitalizations for
pneumonia, and 60,000 cases of invasive disease,
including 3300 cases of meningitis16
. After a vaccine was
introduced in 2002, the rate of the invasive disease
dropped from 21-33 cases per 100,000 population to 13
cases per 100,000 population16
. Pneumonia is treated
with antibiotics, such as macrolides, quinolones, and
nafcillin. However, drug resistant S. pneumonia has
increased. In 1992, 13,300 hospital patients died of
bacterial infections that were resistant to antibiotic
treatment. Today, 6.6 percent of pneumococcus
(penicillin-resistant S. pneumoniae) strains are drug
resistant17
.
3. Quorum Sensing (QS)
The rapid increase of antibiotic resistant pathogenic
bacteria calls for a new strategy that will fight bacteria
without actually killing the bacteria itself. To develop
such a method, we must first understand how single
celled bacteria can cause such widespread damage.
Bacteria communicate with each other and act in groups
through the process of quorum sensing. By this
mechanism, each individual bacterium produces
signaling molecules called autoinducers (AIs). When
these autoinducers reach a certain amount, each
bacterium senses the autoinducers and recognizes that it
is surrounded by other bacteria. Then, all the bacteria
switch gene expression and act in unison. Thus, when
cell density is low, bacterium lives as an individual
without communication; when cell density reaches a
certain level, the quorum sensing mechanism is activated
and bacteria exhibit synchronized behavior as shown in
Fig. 1. Virulent bacteria cause damage when quorum
sensing results in the release of pathogenic factors
including toxins, biofilm formation22-24
, and tissue
attachment factors . Disruption of quorum sensing
systems has been shown to effectively compromise the
infectivity of several pathogenic bacteria. In mice,
mutant quorum sensing-deficient intranasal
Streptococcus pneumonia infections are less capable of
Fig. 1. Bacterial QS system
spreading to the lungs and bloodstream29
. In an infant rat
infection model, a quorum sensing-deficient Neisseria
meningitidis strain is unable to produce living bacteria in
the blood30
. Moreover, quorum sensing exists in bacteria
and certain plants, but not in mammals. Therefore, anti-
quorum sensing antibiotics would effectively target
virulent bacteria without compromising human health 31
.
Because such antibiotics would not kill bacteria,
development of drug resistance is unlikely.
4. MTAN’s role in autoinducer production
5’ –Methylthioadelynosine/ S-adenosylhomocysteine
nucleosidase (MTAN) is a dual substrate enzyme in
bacteria that catalyzes the hydrolytic reactions of 5’ –
Methylthioadenosine (MTA) and S-
adenosylhomocysteine nucleosidase (SAH). S-
adenosylmethionine (SAM) pathways lead to polyamine
synthesis which yields MTA, and methyltransferase
reactions which yield SAH. Polyamines are critical for
bacterial cell growth and methyltransferase reactions are
crucial for cell survival. By inhibiting MTAN, excess
MTA and SAH would accumulate and inhibit their
respective pathways. Furthermore, MTAN plays a key
role in the production of autoinducers. AHL synthase
transfers the amino acid moiety of SAM to an acyl
acceptor to yield acylhomoserine lactones (AI-1), and
produces MTA as a byproduct 32
. MTAN catalyzes the
hydrolytic reaction of SAH to form S-
ribosylhomocysteine (SRH), which is the precursor to
AI-2. MTAN
3
Autoinducer
Pathogenic factors
Low Cell Density High Cell Density

4. 4
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Fig. 2. MTAN’s role in autoinducer production
inhibition would accumulate MTA which would inhibit
AI-1 production, and directly block the formation of
SRH, a precursor to AI-235
. The blockage of both AI-1
and AI-2 would disrupt quorum sensing.
4.1 MTAN as a possible target
As of today, MTAN is only found in prokaryotic cells
and some plants, while mammalian cells utilize another
enzyme, 5’ –Methylthioadelynosine phosphorylase
(MTAP), to consume MTA. MTAP utilizes inorganic
phosphate instead of water to cleave the glycosidic bond
of MTA, yielding adenine and methylthioribose
phosphate. In contrast to MTAN, it does not use S-
adenosylhomocysteine as a substrate. The crystal
structure of human MTAP is available and it is
structurally similar to prokaryotic MTANs . However,
MTAP has a smaller binding pocket for the 5’ region of
the substrate, discriminating the binding of S-
adenosylhomocysteine40
. Thus, inhibitors with a large 5’
substitution would only bind to MTAN, without
inhibiting human MTAP. In theory, inhibitors specific
for SaMTAN could be a potential antibiotic with little or
no interaction with human enzymes.
A new menaquinone pathway was suggested in H.pylori
and C.jejuni recently 41-43
. MTAN was shown to be
essential in the pathway. In contrast to the inhibition of
quorum sensing in other bacteria 44
, inhibition of MTAN
of H.pylori using tight inhibitor leads to growth arrest 45
.
Because this new pathway exists in only few bacteria,
not in human or normal flora, MTAN specific inhibitors
are expected to exhibit few side effects. In addition, low
drug resistance is also expected due to the rarity of the
pathway.
Fig. 3. MTAN’s critical role in the menaquonone pathway
5. CONCLUSION
MTAN’s critical role in bacterial pathways makes it a
possible target for future antibiotics. Inhibiting MTAN
should reduce bacteria toxicity and not lead to drug
4
O
OHOH
O
HOOC
OH
N
NN
N
NH2
O
OHOH
O
HOOC
MTAN (MqnB)
N
NN
N
NH2
O
OHOH
HO +
OH
O
COOH
COOH
CH2
chorismate
MqnA
6-amino-6-deoxyfutalosine
dehypoxanthinylfutalosine
O
HOOC
O
HO
OH
OH
R
O
O
HOOC
OH
OH
menaquinone
MqnC
MqnD
N
N
N
NH2
N
OH
S
BuT-DADMe-ImmA
inhibitor
cyclic dehypoxanthinylfutalosine
1,4-dihydroxy-6-naphthoate
O
N
N N
N
NH2
OHHO
Acyl-ACP
O
O
NH
O
R
AI-1 : AHL
O
N
N N
N
NH2
OHHO
H2O Adenine O
OHHO
OH
S
O
NH2
Methionine
Putrescine CO2 +
polyamines
AHL synthase
H2N
COOH
O
N
N N
N
NH2
OHHO
S
H2O Adenine
H2N
COOH
O
OH
OHHO
S
SH
O
NH2
O O
R
O
HO
HO
HO
HO
LuxS
Homocysteine
S
CH3
AI-2
MTA
SAM
MTR
MTAN
S
SH
H2N
HOOC
SAH
SRH

5. 5
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resistance.
Use same font size for the content of acknowledgements
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________________________________________
REFERENCES (Heading 6)
Use the author/date system of references. In the text refer
to the authors’ name (without initials) and year of
publication. All publications cited in the text should be
pre
sented in a list of references following the text of the
manuscript.
1. Examples for a single author
Peterson (1993) has shown that ……This is in agreement
with the results obtained by several authors (Kramer,
1994; Smith, 1995; Brown, 1999)
2. Examples for two authors
Smith and White (1999) reported that…….This was later
found to be incorrect (Amir and Ahmed, 2000)”.
3. Examples for three or more authors
Moore et al. (1990) stated that …..Similar results were
reported recently (Smith et al., 2003).
The list of references should include only those cited in
the manuscript and arranged alphabetically by authors’
names. Titles of journals should be given in full. ‘In
press' can only be used to cite manuscripts actually
accepted for publication in a journal. Citations such as
‘manuscript in preparation' or ‘manuscript submitted' are
not permitted. Authors must provide Digital Object
Identifier (DOI) number for all references. If there is no
DOI for any reference, author may provide its
URL/direct accessible web link for verification purpose.
References without DOI or internet link are not
acceptable. The following format should be adhered to.
1. Journal Papers
Calik, P., P. Yilgora, P. Ayhanb and A.S. Demir. 2004.
Oxygen transfer effects on recombinant
benzaldehyde lyase production. Chemical
Engineering and Science, 59 (22-23): 5075-5083.
DOI:10.1016/j.ces.2004.07.070.
2. Text Book
Navabi, Z., 1998. Analysis and Modeling of Digital
Systems. 2nd Ed. McGraw Hill, New York. ISBN:
0070464790, pp: 632.
3. Book Chapter
Katz, R.H., 1986. Computer-Aided Design Databases.
In: New Directions for Database Systems, Ariav, G.
and J. Clifford, (Eds.), Intellect Books, Norwood, NJ,
pp: 110-123. ISBN: 0893913448.
4. Conference Proceedings
Magott, J. and K. Skudlarski, 1989. Combining
Generalized Stochastic Petri Nets and PERT
Networks For The Performance Evaluation Of
Concurrent Processes. Proceedings of the 3rd
International Workshop on Petri Nets and
Performance Models, Dec. 11-13, IEEE Xplore Press,
Japan, pp: 249-256. DOI:
10.1109/PNPM.1989.68558.
5. Government Publications
United Nations, 2001. Indicators of Sustainable
Development: Guidelines and Methodologies. United
Nations Press, New York, USA.
6. Online Publications
Lal, R., 1995. Sustainable Management of Soil
Resources in the Humid Tropics. United Nations
University Press, Tokyo, Japan.
http://www.unu.edu/unupress/unupbooks/uu27se/uu2
7se00.htm (Accessed on March 17, 2011)
7. Generic Website
UNEP, 2002. Cleaner Production Assessment in
Industries. Production and Consumption Branch.
United Nations Environment Program.
http://www.unepie.org/pc/cp/understanding_cp/cp_in
dustries.htm (Accessed on February 13, 2011)
8. Theses
Alkoaik, F., 2005. Fate of plant pathogens and pesticides
during composting of greenhouse tomato plant
residues. Unpublished dissertation in partial
fulfillment of the requirements for the degree of
Doctor of Philosophy, Dalhousie University, Halifax,
Nova Scotia, Canada.
5

6. 5
AJBB
A. Name (of the first author) et al. / American Journal of Biochemistry and Biotechnology * (2012) **-**
resistance.
Use same font size for the content of acknowledgements
section.
________________________________________
REFERENCES (Heading 6)
Use the author/date system of references. In the text refer
to the authors’ name (without initials) and year of
publication. All publications cited in the text should be
pre
sented in a list of references following the text of the
manuscript.
1. Examples for a single author
Peterson (1993) has shown that ……This is in agreement
with the results obtained by several authors (Kramer,
1994; Smith, 1995; Brown, 1999)
2. Examples for two authors
Smith and White (1999) reported that…….This was later
found to be incorrect (Amir and Ahmed, 2000)”.
3. Examples for three or more authors
Moore et al. (1990) stated that …..Similar results were
reported recently (Smith et al., 2003).
The list of references should include only those cited in
the manuscript and arranged alphabetically by authors’
names. Titles of journals should be given in full. ‘In
press' can only be used to cite manuscripts actually
accepted for publication in a journal. Citations such as
‘manuscript in preparation' or ‘manuscript submitted' are
not permitted. Authors must provide Digital Object
Identifier (DOI) number for all references. If there is no
DOI for any reference, author may provide its
URL/direct accessible web link for verification purpose.
References without DOI or internet link are not
acceptable. The following format should be adhered to.
1. Journal Papers
Calik, P., P. Yilgora, P. Ayhanb and A.S. Demir. 2004.
Oxygen transfer effects on recombinant
benzaldehyde lyase production. Chemical
Engineering and Science, 59 (22-23): 5075-5083.
DOI:10.1016/j.ces.2004.07.070.
2. Text Book
Navabi, Z., 1998. Analysis and Modeling of Digital
Systems. 2nd Ed. McGraw Hill, New York. ISBN:
0070464790, pp: 632.
3. Book Chapter
Katz, R.H., 1986. Computer-Aided Design Databases.
In: New Directions for Database Systems, Ariav, G.
and J. Clifford, (Eds.), Intellect Books, Norwood, NJ,
pp: 110-123. ISBN: 0893913448.
4. Conference Proceedings
Magott, J. and K. Skudlarski, 1989. Combining
Generalized Stochastic Petri Nets and PERT
Networks For The Performance Evaluation Of
Concurrent Processes. Proceedings of the 3rd
International Workshop on Petri Nets and
Performance Models, Dec. 11-13, IEEE Xplore Press,
Japan, pp: 249-256. DOI:
10.1109/PNPM.1989.68558.
5. Government Publications
United Nations, 2001. Indicators of Sustainable
Development: Guidelines and Methodologies. United
Nations Press, New York, USA.
6. Online Publications
Lal, R., 1995. Sustainable Management of Soil
Resources in the Humid Tropics. United Nations
University Press, Tokyo, Japan.
http://www.unu.edu/unupress/unupbooks/uu27se/uu2
7se00.htm (Accessed on March 17, 2011)
7. Generic Website
UNEP, 2002. Cleaner Production Assessment in
Industries. Production and Consumption Branch.
United Nations Environment Program.
http://www.unepie.org/pc/cp/understanding_cp/cp_in
dustries.htm (Accessed on February 13, 2011)
8. Theses
Alkoaik, F., 2005. Fate of plant pathogens and pesticides
during composting of greenhouse tomato plant
residues. Unpublished dissertation in partial
fulfillment of the requirements for the degree of
Doctor of Philosophy, Dalhousie University, Halifax,
Nova Scotia, Canada.
5