Biased inheritance protects
older bacteria from harm
Asymmetric distribution of an efflux pump makes
older bacteria less sensitive to antibiotics
By Theresa C. Barrett,1,2 Wendy
W. K. Mok,3 Mark P. Brynildsen1,3
In clonal bacterial cultures, where all cells are genetically identical, individual bac- teria can nevertheless express different raits, giving rise to a diverse and com- plex population of phenotypic variants. This phenotypic heterogeneity allows
single organisms to survive in conditions that
are lethal for most of the population, such as
assault with antibiotics (1). The survivors can
then live on and regenerate the population
when conditions become favorable again.
To prevent this type of antibiotic failure, a
greater understanding of the mechanisms
that underlie phenotypic heterogeneity is essential. On page 311 of this issue, Bergmiller
et al. (2) uncover such a mechanism.
The authors study the partitioning of the
AcrAB-TolC multidrug efflux pump in Esch-
erichia coli. This ternary complex spans the
entire cell envelope and provides a route for
direct expulsion of harmful chemicals, such
as numerous antibiotics, from cells (3). TolC
is an outer membrane protein (OMP), and
biogenesis of OMPs is highest in the middle
of the cell, which pushes older OMPs toward
the cell poles (4). As the population divides,
the initial round of division [from generation
0 (G0) to generation 1 (G1)] gives rise to two
“sister cells,” each with an old cell pole that
originated from G0 and a newly formed cell
pole (see the figure). During the next round
of division (G1 to G2), both progeny inherit a
new pole, but their other poles will not be of
the same age. One sister cell will inherit the
older cell pole from G0, whereas the other will
inherit the cell pole from G1. As cells continue
to grow and divide, this asymmetrical distri-
bution gives rise to a subset of cells with in-
creasingly older poles.
Bergmiller et al. monitored the partitioning dynamics of AcrAB-TolC complexes during cell division using fluorescently labeled
AcrB and TolC, as well as a microfluidic
device called the “mother machine.” The
mother machine consists of a series of narrow growth channels that are closed at one
end and open at the other to growth media
that is flowing orthogonal to the channel (5).
As bacteria divide in a channel, the mother
cell (that is, a sister cell that retains the same
aging pole over many generations) remains
captured at the closed end of the channel. At
the other end of the channel, daughter cells
are pushed into the flow and carried away.
With this device, Bergmiller et al. were able
to track pole age. They observed that AcrAB-TolC complexes distribute unequally upon
cell division, with greater abundances in
older poles. Using a Hoechst dye, which can
be expelled by the AcrAB-TolC system, the authors found that mother cells had greater efflux capabilities than daughter cells. Notably,
this characteristic depended on the presence
of AcrAB-TolC complexes (see the figure).
To explore this phenotypic variability further, Bergmiller et al. exposed E. coli to increasing subinhibitory concentrations of
tetracycline, a substrate of the AcrAB-TolC
complex. Daughter cells had a greater change
in both elongation rate and cell cycle duration than mother cells, and this disparity
depended on the presence of the AcrAB-TolC
pump. The authors observed similar effects
for other ribosome-inhibiting antibiotics
that are also substrates for AcrAB-TolC. To
complement these experimental data, the authors developed a simple stochastic model of
this phenomenon that captures their observations and provides a means to assess how
biased partitioning can affect phenotypic
variability at the population level.
Bergmiller et al. thus demonstrate con-
vincingly that asymmetrical segregation of
an OMP at cell division can result in phe-
notypic heterogeneity that has functional
1Department of Molecular Biology, Princeton University,
Princeton, NJ 08544, USA. 2Rutgers Robert Wood Johnson
Medical School, Piscataway, NJ 08854, USA. 3Department of
Chemical and Biological Engineering, Princeton University,
Princeton, NJ 08544, USA. Email: email@example.com
spins at opposite sides of each surface point
in different directions, leaving the overall
magnetic moment equal to zero. The Fermi
surfaces also distort along the direction perpendicular to the plane of the figure, making
it an important new member of a larger class
of “nematic” instabilities, the quantum analog of nematic liquid crystals (5). Just as magnetic order causes magnetostriction in iron,
this nematic order could cause the structural
change in Cd2Re2O7.
Harter et al. tested Fu’s proposal by shining a red laser at a Cd2Re2O7 crystal and
studying the properties of the reflected light.
Through a process called optical second-harmonic generation, materials that lack
inversion symmetry can convert red light
into blue (a trick that is also used to make
green and blue laser pointers). Moreover, the
material symmetry can be further classified
according to the polarization dependence of
the optical second-harmonic signal. Previously, such measurements had identified a
signal that could be associated with the low-symmetry crystal structure; with improved
experimental techniques, Harter et al. found
that a new signal emerges, just below the
transition temperature, with a qualitatively
different symmetry. Both signals disappear
above the transition, but at the transition,
the new signal dominates; thus, the driving
force behind the 200 K transition in Cd2Re2O7
is not crystallographic change, but something
else. Although the results do not identify the
something else with nematic order specifically, all evidence points to it.
Now the fun starts. The optical measurements clearly reveal a new symmetry, but
through an average over spin and momentum that will require further experiments to
resolve. The results also imply that Cd2Re2O7
possesses yet another type of order that remains unobserved, so the search for this is
now on. Cd2Re2O7 is a superconductor below 1 K, so we will be able to see how this
state relates to the spin-momentum order in
the electrons (6). Last, the discovery adds to
growing evidence that nematic order is important in a wide range of solids, including
iron-based and copper-oxide high-temperature superconductors. Indeed, recent optical
second-harmonic results show that inversion symmetry is also broken in the mysterious pseudogap phase of high-temperature
copper-oxide superconductors (7). j
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2. J. W.Harter et al., Science 356, 295(2017).
3. J. C. Petersen et al. , Nat. Phys .2, 605 (2006).
4. L. Fu, Phys. Rev. Lett. 115, 026401 (2015).
5. E. Fradkin et al., Annu. Rev. Condens. Matter Phys. 1, 153
6. V. Kozii, L. Fu, Phys.Rev.Lett. 115, 207002 (2015).
7. L. Zhao et al. , Nat. Phys. 13, 250 (2017).
…can result in phenotypic
heterogeneity that has
functional consequences for