INSIGHTS | PERSPECTIVES
248 21 APRIL 2017 • VOL 356 ISSUE 6335 sciencemag.org SCIENCE
By Jay F. Storz1 and Grant B. McClelland2
When faced with a reduced availabil- ity of oxygen in the environment (hypoxia), vertebrates can make a variety of respiratory, cardiovascu- lar, and hematological adjustments to ensure an uninterrupted supply
of oxygen to the cells of metabolizing tissues (1, 2). These are adaptive solutions for
“aerobic organisms in an aerobic world” (3).
Coping with the complete absence of oxygen
(anoxia) requires more fundamental alterations of cellular metabolism that are typically
nothing more than emergency stopgap measures to buy time until the oxygen supply is
(hopefully) reestablished (4). On page 307 of
this issue, Park et al. (5) identify a new champion of anoxia tolerance among mammals—
the naked mole-rat.
The mammalian brain is especially sensitive to oxygen deprivation because of its
high mass-specific rate of energy metabolism, which is fueled by plasma-derived glucose as a carbon and energy source. Because
the delivery of glucose and oxygen to neurons is closely coupled to energy demand,
oxygen in the brain lasts for only seconds
after the cessation of blood flow, and the
supply of the energy-carrying molecule
adenosine triphosphate (ATP) is depleted
within 1 to 2 min (6). When the ATP supply is no longer sufficient to maintain cellular ion homeostasis, depolarization of cell
membranes leads to necrotic or apoptotic
cell death (4, 7). Consequently, most vertebrates can survive for no more than a few
minutes under anoxia.
There exist, however, a few ectothermic
vertebrates that can survive for months un-
der complete anoxia. These include North
American freshwater turtles (genera Trache-
1School of Biological Sciences, University of Nebraska, Lincoln,
NE 68588, USA. 2Department of Biology, McMaster University,
Hamilton, ON L8S 4K1, Canada. Email: firstname.lastname@example.org
consequences for bacterial populations in
the presence of antibiotics. The results add
to the growing body of knowledge on how
phenotypic variation can contribute to antibiotic failure and resistance development.
For example, Aldridge et al. found that in mycobacteria, elongation preferentially occurs
at old cell poles; this asymmetrical growth,
combined with a time-dependent (rather
than size-dependent) cell division cycle, gives
rise to a population with heterogeneous sizes,
elongation rates, and responses to different
classes of antibiotics (6).
Another type of phenotypic variation that
has emerged as a potentially major contributor to antibiotic treatment failure is bacterial
persistence. Persisters are subpopulations of
bacteria within isogenic cultures that exhibit
extreme tolerance toward bactericidal antibiotics that kill their kin. Several studies have
linked heterogeneous levels of metabolites (7,
8) and other cellular components to this form
of antibiotic tolerance. Pu et al. found that
E. coli persisters tolerant to b-lactams
showed higher expression of efflux genes,
including tolC, which resulted in enhanced
efflux activity and decreased drug accumulation (9). Wakamoto et al. discovered that
persistence to isoniazid in Mycobacterium
smegmatis is a dynamic state governed by
stochastic differences in expression of the
drug-activating enzyme (10). More recently,
mutations that enhance persistence, which
can arise rapidly during cyclic antibiotic exposure (11, 12), have been found to foster development of antibiotic resistance (12).
Although understanding of phenotypic het-
erogeneity and its functional consequences
has increased dramatically in the past 15
years, many questions remain. For example,
it is uncertain to what extent phenotypic het-
erogeneity drives resistance development in
different species and to different drugs. In
biotechnology, it is unclear how phenotypic
heterogeneity and its impact on metabolism
compromises or benefits productivity. With
respect to the findings of Bergmiller et al.,
future studies could focus on other OMPs
that accumulate in aging poles and explore
how their asymmetrical distribution affects
fitness in different ecological niches. Such
knowledge will help determine how phe-
notypic heterogeneity can be targeted to
achieve desirable outcomes, especially for the
challenging task of improving treatments for
bacterial infections. j
REFERENCES AND NOTES
1. N. R. Cohen et al., Cell Host Microbe13, 632 (2013).
2. T. Bergmiller et al., Science356, 311 (2017).
3. D. Du et al ., Nature 509, 512 (2014).
4. P. Rassam et al ., Nature 523, 333 (2015).
5. P. Wang et al. , Curr. Biol. 20, 1099 (2010).
6. B.B.Aldridge et al., Science335,100(2012).
7. E. Germain et al., Mol. Cell 52, 248 (2013).
8. S. M. Amato, M. A. Orman, M. P. Brynildsen, Mol. Cell 50,
9. Y. Pu et al. , Mol. Cell 62, 284 (2016).
10. Y. Wakamoto et al., Science 339, 91 (2013).
11. B. Van den Bergh et al., Nat. Microbiol. 1, 16020 (2016).
12. I.Levin-Reisman etal.,Science 355,826(2017).
T.C.B. and W.W.K.M. contributed equally to this work and
are listed in alphabetical order. This work was supported
by the National Institute of Allergy and Infectious Diseases
(grant F30AI114163), the U. S. Army Research Office (grant
W911NF-15-1-0173), and the Charles H. Revson Foundation.
G0 G0 cell pole
G1 cell pole
G2 cell pole
G1 daughter cell pole
G2 daughter cell pole
Naked mole-rats evolved
a means to cope with anoxia
Age-dependent distribution of efflux pumps
As a bacterial population divides, “mother cells” inherit an increasingly older cell pole and a greater number of
efflux pumps, which increases their efflux capacity and fitness in the presence of antibiotics.