TY - DATA
AB - Phenomenological relations such as Ohm’s or Fourier’s law have a venerable history in physics but are still scarce in biology. This situation restrains predictive theory. Here, we build on bacterial “growth laws,” which capture physiological feedback between translation and cell growth, to construct a minimal biophysical model for the combined action of ribosome-targeting antibiotics. Our model predicts drug interactions like antagonism or synergy solely from responses to individual drugs. We provide analytical results for limiting cases, which agree well with numerical results. We systematically refine the model by including direct physical interactions of different antibiotics on the ribosome. In a limiting case, our model provides a mechanistic underpinning for recent predictions of higher-order interactions that were derived using entropy maximization. We further refine the model to include the effects of antibiotics that mimic starvation and the presence of resistance genes. We describe the impact of a starvation-mimicking antibiotic on drug interactions analytically and verify it experimentally. Our extended model suggests a change in the type of drug interaction that depends on the strength of resistance, which challenges established rescaling paradigms. We experimentally show that the presence of unregulated resistance genes can lead to altered drug interaction, which agrees with the prediction of the model. While minimal, the model is readily adaptable and opens the door to predicting interactions of second and higher-order in a broad range of biological systems.
AU - Kavcic, Bor
ID - 8930
KW - Escherichia coli
KW - antibiotic combinations
KW - translation
KW - growth laws
KW - drug interactions
KW - bacterial physiology
KW - translation inhibitors
TI - Analysis scripts and research data for the paper "Minimal biophysical model of combined antibiotic action"
ER -
TY - GEN
AB - Combining drugs can improve the efficacy of treatments. However, predicting the effect of drug combinations is still challenging. The combined potency of drugs determines the drug interaction, which is classified as synergistic, additive, antagonistic, or suppressive. While probabilistic, non-mechanistic models exist, there is currently no biophysical model that can predict antibiotic interactions. Here, we present a physiologically relevant model of the combined action of antibiotics that inhibit protein synthesis by targeting the ribosome. This model captures the kinetics of antibiotic binding and transport, and uses bacterial growth laws to predict growth in the presence of antibiotic combinations. We find that this biophysical model can produce all drug interaction types except suppression. We show analytically that antibiotics which cannot bind to the ribosome simultaneously generally act as substitutes for one another, leading to additive drug interactions. Previously proposed null expectations for higher-order drug interactions follow as a limiting case of our model. We further extend the model to include the effects of direct physical or allosteric interactions between individual drugs on the ribosome. Notably, such direct interactions profoundly change the combined drug effect, depending on the kinetic parameters of the drugs used. The model makes additional predictions for the effects of resistance genes on drug interactions and for interactions between ribosome-targeting antibiotics and antibiotics with other targets. These findings enhance our understanding of the interplay between drug action and cell physiology and are a key step toward a general framework for predicting drug interactions.
AU - Kavcic, Bor
AU - Tkačik, Gašper
AU - Bollenbach, Tobias
ID - 7673
T2 - bioRxiv
TI - A minimal biophysical model of combined antibiotic action
ER -
TY - JOUR
AB - Most bacteria accomplish cell division with the help of a dynamic protein complex called the divisome, which spans the cell envelope in the plane of division. Assembly and activation of this machinery are coordinated by the tubulin-related GTPase FtsZ, which was found to form treadmilling filaments on supported bilayers in vitro1, as well as in live cells, in which filaments circle around the cell division site2,3. Treadmilling of FtsZ is thought to actively move proteins around the division septum, thereby distributing peptidoglycan synthesis and coordinating the inward growth of the septum to form the new poles of the daughter cells4. However, the molecular mechanisms underlying this function are largely unknown. Here, to study how FtsZ polymerization dynamics are coupled to downstream proteins, we reconstituted part of the bacterial cell division machinery using its purified components FtsZ, FtsA and truncated transmembrane proteins essential for cell division. We found that the membrane-bound cytosolic peptides of FtsN and FtsQ co-migrated with treadmilling FtsZ–FtsA filaments, but despite their directed collective behaviour, individual peptides showed random motion and transient confinement. Our work suggests that divisome proteins follow treadmilling FtsZ filaments by a diffusion-and-capture mechanism, which can give rise to a moving zone of signalling activity at the division site.
AU - Baranova, Natalia S.
AU - Radler, Philipp
AU - Hernández-Rocamora, Víctor M.
AU - Alfonso, Carlos
AU - Lopez Pelegrin, Maria D
AU - Rivas, Germán
AU - Vollmer, Waldemar
AU - Loose, Martin
ID - 7387
JF - Nature Microbiology
SN - 2058-5276
TI - Diffusion and capture permits dynamic coupling between treadmilling FtsZ filaments and cell division proteins
ER -
TY - JOUR
AB - We give a Wong-Zakai type characterisation of the solutions of quasilinear heat equations driven by space-time white noise in 1 + 1 dimensions. In order to show that the renormalisation counterterms are local in the solution, a careful arrangement of a few hundred terms is required. The main tool in this computation is a general ‘integration by parts’ formula that provides a number of linear identities for the renormalisation constants.
AU - Gerencser, Mate
ID - 7388
IS - 3
JF - Annales de l'Institut Henri Poincaré C, Analyse non linéaire
SN - 0294-1449
TI - Nondivergence form quasilinear heat equations driven by space-time white noise
VL - 37
ER -
TY - JOUR
AB - Recently Kloeckner described the structure of the isometry group of the quadratic Wasserstein space W_2(R^n). It turned out that the case of the real line is exceptional in the sense that there exists an exotic isometry flow. Following this line of investigation, we compute Isom(W_p(R)), the isometry group of the Wasserstein space
W_p(R) for all p \in [1,\infty) \setminus {2}. We show that W_2(R) is also exceptional regarding the
parameter p: W_p(R) is isometrically rigid if and only if p is not equal to 2. Regarding the underlying
space, we prove that the exceptionality of p = 2 disappears if we replace R by the compact
interval [0,1]. Surprisingly, in that case, W_p([0,1]) is isometrically rigid if and only if
p is not equal to 1. Moreover, W_1([0,1]) admits isometries that split mass, and Isom(W_1([0,1]))
cannot be embedded into Isom(W_1(R)).
AU - Geher, Gyorgy Pal
AU - Titkos, Tamas
AU - Virosztek, Daniel
ID - 7389
IS - 8
JF - Transactions of the American Mathematical Society
KW - Wasserstein space
KW - isometric embeddings
KW - isometric rigidity
KW - exotic isometry flow
SN - 00029947
TI - Isometric study of Wasserstein spaces - the real line
VL - 373
ER -