which the NAD+ concentration becomes rate
limiting for other vital pathways, including
DNA repair in the nucleus [induced by poly
(ADP-ribose) polymerase 1 (PARP1)] and
activation of sirtuins, the NAD+-dependent
deacetylases implicated in aging (8) that also
activate the mitochondrial unfolded protein
response. Elegant in vitro studies have dem-
onstrated that NAD+ increase allows cultured
cells to grow when treated with inhibitors of
oxidative phosphorylation that would other-
wise arrest cell growth. This clearly demon-
strates that NAD+/NADH imbalance, rather
than ATP depletion, is the crucial insult con-
sequent to inhibiting oxidative phosphoryla-
tion (9). Given that mitochondrial function
was not directly addressed by Williams et al.,
it will be important to determine whether
improved oxidative phosphorylation un-
derlies the remarkable protective effects of
Another surprising finding by Williams et
al. is that the higher dose of dietary nicotinamide not only reversed the aging phenotype
in the retina and protected retinal ganglion
cells when eye pressure was increased, but
also decreased eye pressure in the glaucoma
mouse model. NAD+ supplementation thus
targets the two major risk factors that predispose to retinal ganglion cell dysfunction
and degeneration in glaucoma. The widespread availability of NAD+ supplements and
good tolerability make this a highly attractive treatment for translating into the clinic
to augment existing therapies for decreasing
eye pressure. In a chronic disease such as
glaucoma, such supplements would need to
be taken for long periods. The Nmnat1 gene
therapy approach provides an alternative for
replenishing NAD+ and is one of the first examples of gene therapy having a robust effect
in a complex disease.
Demonstration of clinical neuroprotec-tion in glaucoma has its challenges, but the
recent United Kingdom Glaucoma Treatment
Study (10) shows that it is feasible to demonstrate a reduction in glaucoma progression
rate within a 1-year time frame. The study
of Williams et al. has additional importance
in validating the generalizability of the glaucoma mouse model for developing ganglion
cell–directed therapies. j
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Fighting the enemy within
Halting the rise in antibiotic-resistant infections requires
drugs that selectively target pathogens in microbiota
By Evelina Tacconelli,1,2 Ingo B.
Autenrieth,3,2 Andreas Peschel4,2
The dynamic microbiota that populate all human body surfaces affect health and disease in complex and often subtle ways. At the same time, human gastrointestinal and respiratory tract microbiota are the reservoirs for most
of the human pathogens that cause invasive
bacterial infections. Antibiotic resistance in
such pathogens has dramatically increased in
recent years, resulting in infections that are
much more difficult to treat (1, 2). To counter
this rise, research and development efforts
must target not only new broad-spectrum
antibiotics, but also decolonization agents
that disrupt the major endogenous reservoirs
of antibiotic-resistant bacterial pathogens
(ARBPs) and reduce the risk of infections
that do not respond to treatment.
ARBPs used to spread mostly among at-risk patients in health care settings. However, the pathogens no longer adhere to this
rule. They spread in the community, colonizing the microbiota of both healthy and
diseased humans, and enter hospitals with
patients on admission.
Community-associated methicillin-resis-tant Staphylococcus aureus (CA-MRSA) was
the first major ARBP to emerge in the community in the mid-1990s (3). It did not remain
an exception. Escherichia coli, Klebsiella
pneumoniae, and other Enterobacteriaceae
expressing extended-spectrum b-lactamases
(ESBLs) are increasingly found in human
microbiota outside the health care system, as
is Clostridium difficile, which is intrinsically
resistant to many antibiotics (4, 5). Intestinal
colonization by carbapenemase-producing
Enterobacteriaceae, Pseudomonas aerugi-nosa, and Acinetobacter baumannii and by
vancomycin-resistant enterococci (VRE) has
increased substantially in hospitalized patients worldwide.
Colonizing ARBPs remain unrecognized
if patients are not routinely screened for
their presence. This is currently not a stan-
dard procedure, except, in some countries,
for MRSA and VRE. However, being ARBP-
colonized increases the risk of a patient ac-
quiring bloodstream or other invasive ARBP
infections substantially. This correlation has
been clearly demonstrated for MRSA (6), and
recent studies indicate that the same holds
true for most types of ARBPs (7, 8).
These findings cast doubt on many established infection control strategies and
raise important questions for microbiological, clinical, and antimicrobial compound
research. In particular, it remains unclear
which selection pressures drive the capaci-ties of ARBPs to prevail in human microbiota outside of the health care system;
whether there are specific reservoirs and
transmission routes (e.g., from livestock
via contaminated food) that need to be
disrupted; whether patients should be
screened for more ARBPs upon hospital
admission; under which circumstances
contact isolation of ARBP-colonized patients will be effective; and whether ARBP
carriers should be decolonized to prevent
infection. All these questions require major
1Division of Infectious Diseases, Department of Internal
Medicine 1, University of Tübingen, 72076 Tübingen, Germany.
2German Center for Infection Research (DZIF), Partner Site,
Tübingen, 72076 Tübingen, Germany. 3Medical Microbiology,
Interfaculty Institute of Microbiology and Infection Medicine,
University of Tübingen, 72076 Tübingen, Germany. 4Infection
Biology, Interfaculty Institute of Microbiology and Infection
Medicine, University of Tübingen, 72076 Tübingen, Germany.
to prevent dissemination
that act only on
to treat acute
Halting antimicrobial resistance
A multifaceted approach is needed to counter
the rise in infections that do not respond to