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Journal ArticleDOI

Hydrodynamics of bacteriophage migration along bacterial flagella

04 Jan 2019-Vol. 4, Iss: 1, pp 013101

Abstract: Bacteriophage viruses infect and replicate within bacteria. Some phages ride along the flagellar filaments used by bacteria for propulsion. Here we confirm a 40-year old hypothesis and show that infection can be induced by hydrodynamic forces due to rotation of flagellar filaments.

Summary (3 min read)

Introduction

  • Hydrodynamics of bacteriophage migration along bacterial flagella Panayiota Katsambaa and Eric Lauga† Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge CB3 0WA, United Kingdom (Dated: November 2, 2018) Bacteriophage viruses, one of the most abundant entities in their planet, lack the ability to move independently.
  • Indeed, phages have been killing bacteria for way longer than humanity has been fighting against bacterial infections, with as many as 1029 infections of bacterial cells by oceanic phages taking place every day [11, 12].
  • Once in contact with a rotating flagellar filament, it is anticipated that the phage fibres will wrap along the short-pitch grooves.
  • The authors in Ref. [27] examined flagellar filaments with different polymorphic forms, since the different arrangements of the flagellin subunits give rise to grooves with different pitch and chirality [25], as shown in Fig. 3B.
  • The hydrodynamic torque actuating the translocation is provided by the parts sticking out in the bulk.

II.1. Geometry

  • As their first model, the authors consider the flagellar filament as a straight, smooth rod aligned with the z-axis and of radius Rfl.
  • The phage has a capsid head of size 2ah, a tail of length Lt and fibres that wrap around the flagellar filament.
  • The helical shape of the fibres has helix angle α, as shown in Fig.
  • Assuming the phage to move rigidly and working in the laboratory frame, every point r on the phage moves with velocity Uez + ωpez ∧ r.
  • The purpose of their calculation is to compute the two unknown quantities, U and ωp, in terms of ωfl by enforcing the overall force and torque balance on the phage along the z-axis.

II.2. Forces and moments

  • In order to calculate the forces and torques acting on the tail and fibres the authors use the resistive-force theory of viscous hydrodynamics (RFT in short) [30, 31].
  • This drag anisotropy is at the heart of the propulsion physics for microorganisms such as bacteria and spermatozoa [31].
  • The symbols ζ⊥,t, ζ‖,t are the drag coefficients for motion perpendicular and parallel to the local tangent, with ζ‖,t ≡ ρtζ⊥,t and the velocity of the tail relative to the fluid is ureltail(s) = ωp (ez ∧ rt) + Uez. (6) For the fibres, the authors use the version of RFT modified to capture the motion of slender rods near a surface.
  • These results are valid in the limit in which the distance d between the fibre and the surface of the flagellar filaments is much smaller than the radius of the flagellar filament (d Rfl), such that the surface of the smooth flagellar filament is locally planar.
  • The authors thus proceed by considering the two limiting geometries of long- and short-tailed phages.

II.4.1. Long-tailed phages

  • The authors use below the χ-phage as a typical long-tailed phage, whose detailed dimensions are reported in Ref. [22].
  • Å between parallel sides (that is 2ah ≈ 650− 675 Å).
  • From this the authors see that they can safely assume that Rfl, ah Lt, Lfib.
  • The authors variables are thus divided into the short lengthscales of ah, Rfl and the long lengthscales of Lfib, Lt. With these approximations the authors obtain the translocation speed as Ulong ≈− hωflRfl(1− ρfib) sinα cosα Glong, (32) Glong = ζ⊥,fibLfib [ 1 3ζ⊥,tLt(1− t 2 z) + [ ζ⊥,tRfltx + 6πµah(1− t2z) ]] 1 3ζ⊥,tLt(1− t2z) [ ζ⊥,tLt [1− (1− ρt)t2z] + ζ⊥,fibLfib(sin2 α+ ρfib cos2 α) ] (33) ≈ ζ⊥,fibLfib[ ζ⊥,tLt [1− (1− ρt)t2z] + ζ⊥,fibLfib(sin2 α+ ρfib cos2 α) ] , (34) with a relative error of O (ah/Lt, ah/Lfib, Rfl/Lt, Rfl/Lfib).
  • Details of the approximation are given in the Supplementary Material (see [35]).

II.4.2. Short-tailed phages

  • Phages with very short tails that use their fibres to wrap around flagellar filaments are equivalent geometrically to phages that use their entire tail for wrapping since in both cases there is a filamentous part of the phage wrapped around the flagellar filament and the head is sticking out in the bulk close to the surface of the filament.
  • In order to avoid any confusion, the authors will carry out the calculations of this section using the geometry of short-tailed phages, and assume that (i) the tail is negligible and (ii) the fibres are wrapping around the flagellar filament.
  • Firstly, and most importantly, both results for the translocation speeds in Eqs. 32 and 35 have the common factor −hRflωfl(1 − ρfib) sinα cosα which is multiplying the positive dimensionless expressions Glong and Gshort respectively.
  • Secondly, the factor (1− ρfib) reveals that translocation requires anisotropy in the friction between the fibres and the surface of the flagellar filament (i.e. ρfib 6= 1).
  • The authors observe that terms involving Lfib appear in both the numerator and denominator of Eq. 34.

III.1. Geometry

  • As a more refined physical model, the authors now include in this section the mechanics arising from the microscopic details of the grooved surface of the flagellar filament due to the packing of the flagellin molecules and modify the previous calculation in order to account for the motion of the phage fibres sliding along the helical grooves.

III.2. Forces and moments

  • The details of the interactions between the phage fibres and the grooves are expected to be complicated as they depend on the parts of the flagellin molecules that make up the groove surface and interact with the proteins that the fibres consist of.
  • These interactions could originate from a number of short range intermolecular forces, for example electrostatic repulsion or Van der Waals forces.
  • The authors model here the resultant of the interaction forces acting on the fibre sliding along the grooves as consisting of two parts, a drag and a restoring force, as shown in the inset of Fig.
  • Finally, from Eq. 60, the translocation velocity along the z-axis is calculated as U = V cosα.
  • III.4. Two limits: long vs short-tailed phages.

III.4.1. Long-tailed phages

  • Under the approximations relevant for long-tailed phages such as χ-phage described in §II.4, i.e. Rfl, ah Lt, Lfib, the translocation velocity along the z-axis gets simplified to Ulong = −hRflωfl sinα cosαGlong, (62) Glong = L2t [ 1 3ζ⊥,tLt + 6πµah ] (1− t2z) L2t [ 1 3ζ⊥,tLt + 6πµah ] (1− t2z) sin2 α+ µ̃R2flLfib · (63) with the details of the approximation given in the Supplementary Material (see [35]).

III.4.2. Short-tail phages

  • In the case of short-tail phages, the authors assume that the tail is negligible and that the fibres are wrapping around the flagellar filament.
  • Interpretation and discussion of the results Similarly to §II.4.3, the authors interpret and compare the results in Eqs. 62 and 64.
  • Here again, the crucial factor −hRflωfl sinα cosα appears in both equations multiplying a positive, non-dimensional expression, and the authors obtain the correct directionality and speed of translocation in agreement with Ref. [27].
  • The presence of the term µ̃R2flLfib in the denominator implies that the sliding drag from the fibre decreases the translocation speed, and longer fibres give a decreased speed.
  • The authors now illustrate the dependence of the translocation speed on the geometrical parameters of the phage, namely Lt and Lfib, according to their model of translocation along grooved flagellar filaments.

IV. CONCLUSION

  • The authors carried out a first-principle theoretical study of the nut-and-bolt mechanism of phage translocation along the straight flagellar filaments of bacteria.
  • The main theoretical predictions from their two models, Eqs. 32, 35, 62 and 64, give the phage translocation speed, U , in terms of the phage and groove geometries and the rotation rate of the flagellar filament, in the two relevant limits of long- and short-tailed phages.
  • The common prefactor in the formulae for the translocation speed along the filament, U ∼ −hωflRfl sinα cosα, appears in the expressions from both models.
  • The authors conjecture that the second model with its explicit inclusion of the grooves should be closer to the real-life situation.
  • The authors hope that the modelling developed in this paper will motivate not only further theoretical studies along those lines but also more experimental work clarifying the processes involved in the wrapping and motion of the fibre in the grooves.

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Hydrodynamics of bacteriophage migration along bacterial flagella
Panayiota Katsamba
a
and Eric Lauga
Department of Applied Mathematics and Theoretical Physics,
University of Cambridge, Cambridge CB3 0WA, United Kingdom
(Dated: November 2, 2018)
Bacteriophage viruses, one of the most abundant entities in our planet, lack the ability to move
independently. Instead, they crowd fluid environments in anticipation of a random encounter with
a bacterium. Once they ‘land’ on the cell body of their victim, they are able to eject their genetic
material inside the host cell. Many phage species, however, first attach to the flagellar filaments
of bacteria. Being immotile, these so-called flagellotropic phages still manage to reach the cell
body for infection, and the process by which they move up the flagellar filament has intrigued the
scientific community for decades. In 1973, Berg and Anderson (Nature, 245, 380-382) proposed
the nut-and-bolt mechanism in which, similarly to a rotated nut that is able to move along a bolt,
the phage wraps itself around a flagellar filament possessing helical grooves (due to the helical
rows of flagellin molecules) and exploits the rotation of the flagellar filament in order to passively
travel along it. One of the main evidence for this mechanism is the fact that mutants of bacterial
species such as Escherichia coli and Salmonella typhimurium that possess straight flagellar filaments
with a preserved helical groove structure can still be infected by their relative phages. Using two
distinct approaches to address the short-range interactions between phages and flagellar filaments,
we provide here a first-principle theoretical model for the nut-and-bolt mechanism applicable to
mutants possessing straight flagellar filaments. Our model is fully analytical, is able to predict the
speed of translocation of a bacteriophage along a flagellar filament as a function of the geometry
of both phage and bacterium, the rotation rate of the flagellar filament, and the handedness of the
helical grooves, and is consistent with past experimental observations.
a
Current address: School of Mathematics, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
e.lauga@damtp.cam.ac.uk

2
Head
Collar
Tail
Long Tail
Fibres
Base Plate
DNA
Protein
2D 3D
FIG. 1. Bacteriophages: (A) A typical morphology of a bacteriophage, such as the Enterobacteria T4 phage (Adenosine,
Wikimedia Commons); (B) Electron micrograph of bacteriophages attached to a bacterial cell, (Dr. G. Beards, Wikimedia
Commons); (C-E) Phages can come in various shapes: (C) Myoviridae; (D) Podoviridae; (E) Siphoviridae [8]. Panels C-E:
Reprinted by permission from Suttle CA, “Viruses in the sea”, Nature, 437 (356), 356-361, Copyright 2005 Springer Nature.
I. INTRODUCTION
As big as a fraction of a micrometre, bacteriophages (in short phages), are ‘bacteria-eating’ viruses (illustrated in
Fig. 1) that infect bacteria and replicate within them [1]. With their number estimated to be of over 10
31
on the
planet, phages are more abundant than every other organism on Earth combined [2–8].
Phages have been used extensively in genetic studies [1, 4, 9], and their future use in medicine is potentially of even
greater impact. The global rise in antibiotic resistance, as reported by the increasing number of multidrug-resistant
bacterial infections [10], poses one of the greatest threats to human health of our times, and phages could offer the
key to resolution. Indeed, phages have been killing bacteria for way longer than humanity has been fighting against
bacterial infections, with as many as 10
29
infections of bacterial cells by oceanic phages taking place every day [11, 12].
Phage therapy is an alternative to antibiotics that has been used for almost a century and offers promising solutions
to tackle antibiotic-resistant bacterial infections [13]. Furthermore, the unceasing phage-bacteria war taking place in
enormous numbers offers the scientific community great opportunities to learn. For example, the ability of phages
to update their infection mechanisms in response to bacterial resistance could offer us valuable insight into updating
antibiotics treatment against multi drug-resistant pathogenic bacteria [14]. In addition, the high selectivity of the
attachment of a phage to the receptors on the bacterial cell surface and the species it infects could help identify possible
target points of particular pathogenic bacteria for drugs to attack [15]. In general, extensive studies of bacteriophage
infection strategies could not only reveal vulnerable points of bacteria, but may help uncover remarkable biophysical
phenomena taking place at these small scales.
Infection mechanisms can vary across the spectrum of phage species [15, 16]. Lacking the ability to move indepen-
dently, phages simply crowd fluid environments and rely on a random encounter with a bacterium in order to land
on its surface and accomplish infection using remarkable nanometre size machinery. Typically, the receptor-binding
proteins located on the long tail fibres recognise and bind to the receptors of the host cell via a two-stage process
called phage adsorption [15]. The first stage is reversible, and is followed by irreversible attachment onto the cell
surface. Subsequently, the genetic material is ejected from their capsid-shaped head, through their tail, which is a
hollow tube, into the bacterium [17, 18].
While all phages need to find themselves on the surface of the cell body for infection to take place, there is a
class of phages, called flagellotropic phages, that first attach to the flagellar filaments of bacteria. Examples include
the χ-phage infecting Escherichia coli (E. coli) and Salmonella typhimurium (Salmonella), the phage PBS1 infecting
Bacillus subtilis (B. subtilis) and the recently discovered phage vB VpaS OWB (for short OWB) infecting Vibrio
parahaemolyticus (V. parahaemolyticus) [19], illustrated in Fig. 2.
Given the fact that phages are themselves incapable of moving independently and that the distance they would have
to traverse along the flagellar filament is large compared to their size, they must find an active means of progressing
along the flagellar filament. In Ref. [22], electron microscopy images of the flagellotropic χ-phage, shown in Figs. 2C
and D, were provided to show that the mechanism by which χ-phage infects E. coli consists of travelling along the
outside of the flagellar filament until it reaches the base of the flagellar filament where it ejects its DNA.
A possible mechanism driving the translocation of χ-phage along the flagellar filament was first proposed in Berg
and Anderson’s seminal paper as the ‘nut-and-bolt’ mechanism [23]. Their paper is best known for establishing that
bacteria swim by rotating their flagellar filaments. One of the supporting arguments was the proposed mechanism

3
FIG. 2. Flagellotropic phages: (A) Attachment of phage OWB to V. parahaemolyticus [19]. Red arrows indicate phage
particles. (B) Phage PBS1 adsorbed to the flagellar filament of a B. Subtilis bacterium with its tail fibres wrapped around the
flagellar filament in a helical shape with a pitch of 35 nm [20]. The phage hexagonal head capsid measures 120 nm from edge
to edge [21]. Reprinted (amended) by permission from American Society for Microbiology from Raimondo LM, Lundh NP,
Martinez RJ, “Primary Adsorption Site of Phage PBS1: the Flagellum of Bacillus”, J. Virol., 1968, 2 (3), 256-264, Copyright
1968, American Society for Microbiology. (C) χ-phage of E. coli [22]. The head measures 65 to 67.5 nm between the parallel
sides of the hexagon [22]; (D) χ-phage at different times between attachment on the flagellar filament of E. coli and reaching
the base of the filament [22]. Arrows point to the bases of the flagella. Panels C-D: Reprinted (amended) by permission from
American Society for Microbiology from Schade SZ, Adler J, Ris H, “How Bacteriophage χ Attacks Motile Bacteria”, J. Virol.,
1967, 1 (3), 599-609, Copyright 1967, American Society for Microbiology.
where the phage plays the role of the nut and the bolt is the flagellar filament, with the grooves between the helical
rows of flagellin molecules making up the flagellar filament serving as the threads [23] (Figs. 3A and B). A phage
would then wrap around the flagellar filament and the rotation of the latter would result in the translocation of the
phage along it.
A mutant of Salmonella that has straight flagellar filaments, but possesses the same helical screw-like surface due
to the arrangement of the flagellin molecules [24] is non-motile due to the lack of chiral shape yet fully sensitive to
χ-phage [26], i.e. the phages manage to get transported to the base of the flagellar filament. This is consistent with
the nut-and-bolt mechanism and was used as evidence that the flagellar filament is rotating [23].
More evidence in support of the nut-and-bolt mechanism were provided 26 years after its inception in a work studying
strains of Salmonella mutants with straight flagellar filaments whose motors alternate from rotating clockwise (CW)
and counter-clockwise (CCW) [27]. The directionality of rotation is crucial to the mechanism as CCW rotation
will only pull the phage toward the cell body if the phage slides along a right-handed groove. In order to test the
directionality, the authors used a chemotaxis signalling protein that interacts with the flagellar motor, decreasing the
CCW bias. They found that strains with a large CCW bias are sensitive to χ-phage infection, whereas those with
small CCW bias are resistant, in agreement with the proposed nut-and-bolt mechanism.
Details of the packing of the flagellin molecules that give rise to the grooves can be found in Ref. [25] and examples
are shown in Figs. 3A and B. It is important to note that the packing of flagellin molecules produces two overlapping
sets of helical grooves, a long-pitch and a short-pitch set of grooves which are of opposite chirality [24]. Once in
contact with a rotating flagellar filament, it is anticipated that the phage fibres will wrap along the short-pitch
grooves. Indeed, the findings of Ref. [27] show that the directionality of phage translocation correlates with the
chirality of the short-pitch grooves.
The flagellar filaments of bacteria can take one of the twelve distinct polymorphic shapes as illustrated in Figs. 3B
and C. The authors in Ref. [27] examined flagellar filaments with different polymorphic forms, since the different
arrangements of the flagellin subunits give rise to grooves with different pitch and chirality [25], as shown in Fig. 3B.
The L-type straight flagellar filament (f0) that was used by Ref. [27] has both left-handed long-pitch grooves and right-
handed short-pitch grooves [24]. Given that the short-pitch grooves are relevant to the wrapping of the fibres, the
findings of Ref. [27] that bacteria with their flagellar filament in the f0 polymorphic state (i.e. with right-handed short-
pitch grooves) and with a large CCW bias are sensitive to χ-phage infection, are in agreement with the nut-and-bolt

4
FIG. 3. Bacterial flagellar filaments and polymorphism: (A) Structure of straight flagellar filament from a mutant of
Salmonella typhimurium [24]. Reprinted with permission from O’Brien EJ, Bennett PM, “Structure of straight flagella from a
mutant Salmonella”, J. Mol. Biol., 70 (1), 145-152, Copyright 1972 Elsevier. The L-type straight flagellar filament (left) has
two types of helical grooves, left-handed long-pitch and right-handed short-pitch grooves, whereas the R-type straight filament
(right) has right-handed long-pitch and left-handed short-pitch grooves. Examples of short-pitch grooves are marked by thin
blue lines and indicated by arrows. (B) Schematic of some polymorphic states of the flagellar filament, from left to right: L-type
straight, normal (left-handed shape), curly (right-handed) and R-type straight. The top panel shows the shape of the filaments
while the bottom panel displays the arrangements of flagellin subunits. Examples of short-pitch grooves are marked by thin
blue lines and indicated by arrows [25]. Reprinted with permission from Namba K, Vonderviszt F, “Molecular architecture of
bacterial flagellum”, Q. Rev. Biophys., 1997, 30 (1), 1-65, Copyright 1997 Cambridge University Press.
mechanism.
The same study also argued that the translocation time of the phage to the cell body is less than the flagellar
filament reversal interval, a necessary condition for successful infection by the virus of wild-type bacteria whose
motors alternate between CCW and CW rotation. Their estimated translocation speeds on the order of microns per
seconds give a translocation time which is less than the CCW time interval of about a 1 s [27].
Relevant to the nut-and-bolt mechanism are also the findings of an alternative mechanism for adsorption of the
flagellotropic phages φCbK and φCb13 that interact with the flagellar filament of Caulobacter crescentus using a
filament located on the head of the phage [28], instead of the tail or tail fibres that other flagellotropic phages use,
such as χ and P BS1. This study also reports on a higher likelihood of infection with a CCW rotational bias that
is consistent with the nut-and-bolt mechanism. Notably, phages can also attach to curli fibres, which are bacterial
filaments employed in biofilms; however due to the lack of helical grooves and rotational motion of these filaments,
phages are unable to move along them [29].
In this paper, we theoretically examine the nut-and-bolt mechanism from a quantitative point of view and perform
a detailed mathematical analysis of the physical mechanics at play. We focus on the virus translocation along straight
flagellar filaments in mutants such as the mutant of Salmonella used in Ref. [23]. A flagellotropic phage can wrap
around a given flagellar filament using its tail fibres (fibres for short), its tail, or in some cases a filament emanating
from the top of its head [28] and the models we develop can address all these relevant morphologies. A schematic
diagram of the typical geometry we consider is shown in Fig. 4.
A phage floating in a fluid whose fibres suddenly collide with a flagellar filament rotating at high frequency will
undergo a short, transient period of wrapping, during which the length of the fibres that are wrapped around the
filament is increasing. In this paper we study the translocation of the phage once it has reached a steady, post-wrapping
state, and assume that it is moving rigidly with no longer any change in the relative virus-filament configuration.
In order to provide first-principle theoretical modelling of the nut-and-bolt mechanism, we build in the paper a
hierarchy of models. In §II, we start with a model of drag-induced translocation along smooth flagellar filaments that
ignores the microscopic mechanics of the grooves yet implicitly captures their effect by coupling the helical shape
of the fibres with anisotropy in motion in the local tangent plane of the flagellar filament. Having acquired insight
into the key characteristics of the mechanism, we proceed by building a refined, more detailed model of the guided

5
FIG. 4. Schematic model of the translocation of a flagellotropic phage along the straight flagellar filament of
a mutant bacterium. The phage, illustrated in dark green, is wrapped around the straight flagellar filament (light blue
cylinder) using its fibres, with its tail and head protruding in the bulk fluid.
translocation of phages along grooved flagellar filaments by incorporating the microscopic mechanics of the grooves in
§III. This is done by including a restoring force that acts to keep the fibres in the centre of the grooves, thereby guiding
their motion, as well as a resistive force acting against the sliding motion. In both models, we proceed by considering
the geometry, and the forces and torques acting on the different parts of the phage. We use the resistive-force theory
of viscous hydrodynamics in order to model the tail and tail fibres which are both slender [30, 31]. The portion of
the phage wrapping around the flagellar filament is typically the fibres. They experience a hydrodynamic drag from
the motion in the proximity of the rotating flagellar filament along which they slide in the smooth flagellum model,
or a combination of a guiding and resistive forces in the grooved flagellum model. Parts sticking out in the bulk away
from the flagellar filament experience a hydrodynamic drag due to their motion in an otherwise stagnant fluid.
We build in our paper a general mathematical formulation relevant to a broad phage morphology. In our typical
geometry of phages wrapping around flagellar filaments using their fibres, two limits arise for long-tailed and short-
tailed phages. Long-tailed phages have their tail and head sticking out in the bulk, away from the flagellar filament,
whereas for short-tailed phages only the head is exposed to the bulk fluid. The hydrodynamic torque actuating the
translocation is provided by the parts sticking out in the bulk.
We compare the results from the two models addressing the two geometrical limits and find these to be consistent
with each other and with the predictions and experimental observations of Refs. [23, 27]. In particular, we predict
quantitatively the speed of phage translocation along the flagellar filament they are attached to, and its critical
dependence on the interplay between the chirality of the wrapping and the direction of rotation of the filament, as
well as the geometrical parameters. Most importantly we show that our models capture the correct directionality of
translocation, i.e. that CCW rotation will only pull the phage toward the cell body if the phage slides along a right-
handed groove, and predict speeds of translocation on the order of µms
1
, which are crucial for successful infection
in the case of bacteria with alternating CCW and CW rotations.
II. DRAG-INDUCED TRANSLOCATION ALONG SMOOTH FLAGELLAR FILAMENTS
II.1. Geometry
As our first model, we consider the flagellar filament as a straight, smooth rod aligned with the z-axis and of radius
R
fl
. The phage has a capsid head of size 2a
h
, a tail of length L
t
and fibres that wrap around the flagellar filament.
We implicitly capture the effect of the grooves (i) by imposing that the fibres that emanate from the bottom of the
tail of the phage are wrapped around the flagellar filament in a helical shape and (ii) via the anisotropy in the drag
arising from the relative motion between the fibres and the rotating flagellar filament. The helical shape of the fibres
has helix angle α, as shown in Fig. 5. With the assumption that the gap between the fibres and the flagellar filament
is negligible compared to the radius R
fl
of the flagellar filament, the centreline r
fib
(s) of the fibres, parametrised by

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Journal ArticleDOI
Jessica M A Blair1, Mark A. Webber1, Alison J. Baylay1, DO Ogbolu1  +1 moreInstitutions (1)
TL;DR: Recent advances in understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics are reviewed, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics.
Abstract: Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This article reviews recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics.

2,096 citations


Journal ArticleDOI
Curtis A. Suttle1Institutions (1)
TL;DR: Viruses are by far the most abundant 'lifeforms' in the oceans and are the reservoir of most of the genetic diversity in the sea, thereby driving the evolution of both host and viral assemblages.
Abstract: If stretched end to end, the estimated 1030viruses in the oceans would span farther than the nearest 60 galaxies. This reservoir of genetic and biological diversity continues to yield exciting discoveries and, in this Review, Curtis A. Suttle highlights the areas that are likely to be of greatest interest in the next few years. Viruses are by far the most abundant 'lifeforms' in the oceans and are the reservoir of most of the genetic diversity in the sea. The estimated 1030 viruses in the ocean, if stretched end to end, would span farther than the nearest 60 galaxies. Every second, approximately 1023 viral infections occur in the ocean. These infections are a major source of mortality, and cause disease in a range of organisms, from shrimp to whales. As a result, viruses influence the composition of marine communities and are a major force behind biogeochemical cycles. Each infection has the potential to introduce new genetic information into an organism or progeny virus, thereby driving the evolution of both host and viral assemblages. Probing this vast reservoir of genetic and biological diversity continues to yield exciting discoveries.

2,067 citations


Journal ArticleDOI
Eric Lauga1, Thomas R. Powers2Institutions (2)
TL;DR: The biophysical and mechanical principles of locomotion at the small scales relevant to cell swimming, tens of micrometers and below are reviewed, with emphasis on the simple physical picture and fundamental flow physics phenomena in this regime.
Abstract: Cell motility in viscous fluids is ubiquitous and affects many biological processes, including reproduction, infection and the marine life ecosystem. Here we review the biophysical and mechanical principles of locomotion at the small scales relevant to cell swimming, tens of micrometers and below. At this scale, inertia is unimportant and the Reynolds number is small. Our emphasis is on the simple physical picture and fundamental flow physics phenomena in this regime. We first give a brief overview of the mechanisms for swimming motility, and of the basic properties of flows at low Reynolds number, paying special attention to aspects most relevant for swimming such as resistance matrices for solid bodies, flow singularities and kinematic requirements for net translation. Then we review classical theoretical work on cell motility, in particular early calculations of swimming kinematics with prescribed stroke and the application of resistive force theory and slender-body theory to flagellar locomotion. After examining the physical means by which flagella are actuated, we outline areas of active research, including hydrodynamic interactions, biological locomotion in complex fluids, the design of small-scale artificial swimmers and the optimization of locomotion strategies. (Some figures in this article are in colour only in the electronic version) This article was invited by Christoph Schmidt.

1,979 citations


Journal ArticleDOI
KE Wommack, Rita R. Colwell1Institutions (1)
TL;DR: Novel applications of molecular genetic techniques have provided good evidence that viral infection can significantly influence the composition and diversity of aquatic microbial communities, supporting the hypothesis that viruses play a significant role in microbial food webs.
Abstract: The discovery that viruses may be the most abundant organisms in natural waters, surpassing the number of bacteria by an order of magnitude, has inspired a resurgence of interest in viruses in the aquatic environment. Surprisingly little was known of the interaction of viruses and their hosts in nature. In the decade since the reports of extraordinarily large virus populations were published, enumeration of viruses in aquatic environments has demonstrated that the virioplankton are dynamic components of the plankton, changing dramatically in number with geographical location and season. The evidence to date suggests that virioplankton communities are composed principally of bacteriophages and, to a lesser extent, eukaryotic algal viruses. The influence of viral infection and lysis on bacterial and phytoplankton host communities was measurable after new methods were developed and prior knowledge of bacteriophage biology was incorporated into concepts of parasite and host community interactions. The new methods have yielded data showing that viral infection can have a significant impact on bacteria and unicellular algae populations and supporting the hypothesis that viruses play a significant role in microbial food webs. Besides predation limiting bacteria and phytoplankton populations, the specific nature of virus-host interaction raises the intriguing possibility that viral infection influences the structure and diversity of aquatic microbial communities. Novel applications of molecular genetic techniques have provided good evidence that viral infection can significantly influence the composition and diversity of aquatic microbial communities.

1,812 citations


Journal ArticleDOI
Curtis A. Suttle1Institutions (1)
15 Sep 2005-Nature
TL;DR: The understanding of the effect of viruses on global systems and processes continues to unfold, overthrowing the idea that viruses and virus-mediated processes are sidebars to global processes.
Abstract: Viruses exist wherever life is found. They are a major cause of mortality, a driver of global geochemical cycles and a reservoir of the greatest genetic diversity on Earth. In the oceans, viruses probably infect all living things, from bacteria to whales. They affect the form of available nutrients and the termination of algal blooms. Viruses can move between marine and terrestrial reservoirs, raising the spectre of emerging pathogens. Our understanding of the effect of viruses on global systems and processes continues to unfold, overthrowing the idea that viruses and virus-mediated processes are sidebars to global processes.

1,673 citations


Performance
Metrics
No. of citations received by the Paper in previous years
YearCitations
20203
20191