Opposing effects of target overexpression reveal drug mechanisms.


:Overexpression of a drug's molecular target often increases drug resistance, offering a pathway for adaptive evolution and a tool for target identification. It is unclear though why this phenomenon applies to some drugs but not others. Here we gradually overexpressed antibiotic targets in Escherichia coli and found that drug resistance can increase, remain unchanged, decrease or even change non-monotonically. Even a single target can produce opposing responses to its different inhibitors. We explain these contradicting effects with quantitative models of enzyme inhibition that account for fitness costs and the biochemical activity or inactivity of drug-enzyme complexes. Thus, target overexpression confers resistance or sensitivity as a predictable property of drug mechanism, explaining its variable presence in nature as a resistance mechanism. Though overexpression screens may fail at identifying unknown targets, overexpressing known or putative targets provides a systematic approach to distinguish between simple inhibition and complex mechanisms of drug action.


Nat Commun


Nature communications


Palmer AC,Kishony R




Has Abstract


2014-07-01 00:00:00










  • Macromolecular and electrical coupling between inner hair cells in the rodent cochlea.

    abstract::Inner hair cells (IHCs) are the primary receptors for hearing. They are housed in the cochlea and convey sound information to the brain via synapses with the auditory nerve. IHCs have been thought to be electrically and metabolically independent from each other. We report that, upon developmental maturation, in mice 3...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Jean P,Anttonen T,Michanski S,de Diego AMG,Steyer AM,Neef A,Oestreicher D,Kroll J,Nardis C,Pangršič T,Möbius W,Ashmore J,Wichmann C,Moser T

    更新日期:2020-06-25 00:00:00

  • LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function.

    abstract::Autophagy perturbation represents an emerging therapeutic strategy in cancer. Although LATS1 and LATS2 kinases, core components of the mammalian Hippo pathway, have been shown to exert tumor suppressive activities, here we report a pro-survival role of LATS1 but not LATS2 in hepatocellular carcinoma (HCC) cells. Speci...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Tang F,Gao R,Jeevan-Raj B,Wyss CB,Kalathur RKR,Piscuoglio S,Ng CKY,Hindupur SK,Nuciforo S,Dazert E,Bock T,Song S,Buechel D,Morini MF,Hergovich A,Matthias P,Lim DS,Terracciano LM,Heim MH,Hall MN,Christofori G

    更新日期:2019-12-17 00:00:00

  • An in vivo platform to select and evolve aggregation-resistant proteins.

    abstract::Protein biopharmaceuticals are highly successful, but their utility is compromised by their propensity to aggregate during manufacture and storage. As aggregation can be triggered by non-native states, whose population is not necessarily related to thermodynamic stability, prediction of poorly-behaving biologics is di...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Ebo JS,Saunders JC,Devine PWA,Gordon AM,Warwick AS,Schiffrin B,Chin SE,England E,Button JD,Lloyd C,Bond NJ,Ashcroft AE,Radford SE,Lowe DC,Brockwell DJ

    更新日期:2020-04-14 00:00:00

  • Visualization of nanocrystal breathing modes at extreme strains.

    abstract::Nanoscale dimensions in materials lead to unique electronic and structural properties with applications ranging from site-specific drug delivery to anodes for lithium-ion batteries. These functional properties often involve large-amplitude strains and structural modifications, and thus require an understanding of the ...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Szilagyi E,Wittenberg JS,Miller TA,Lutker K,Quirin F,Lemke H,Zhu D,Chollet M,Robinson J,Wen H,Sokolowski-Tinten K,Lindenberg AM

    更新日期:2015-03-12 00:00:00

  • Multiscale real time and high sensitivity ion detection with complementary organic electrochemical transistors amplifier.

    abstract::Ions are ubiquitous biological regulators playing a key role for vital processes in animals and plants. The combined detection of ion concentration and real-time monitoring of small variations with respect to the resting conditions is a multiscale functionality providing important information on health states. This mu...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Romele P,Gkoupidenis P,Koutsouras DA,Lieberth K,Kovács-Vajna ZM,Blom PWM,Torricelli F

    更新日期:2020-07-27 00:00:00

  • Quantum speedup in the identification of cause-effect relations.

    abstract::The ability to identify cause-effect relations is an essential component of the scientific method. The identification of causal relations is generally accomplished through statistical trials where alternative hypotheses are tested against each other. Traditionally, such trials have been based on classical statistics. ...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Chiribella G,Ebler D

    更新日期:2019-04-01 00:00:00

  • Breakdown of energy transfer gap laws revealed by full-dimensional quantum scattering between HF molecules.

    abstract::Inelastic collisions involving molecular species are key to energy transfer in gaseous environments. They are commonly governed by an energy gap law, which dictates that transitions are dominated by those between initial and final states with roughly the same ro-vibrational energy. Transitions involving rotational ine...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Yang D,Huang J,Hu X,Guo H,Xie D

    更新日期:2019-10-11 00:00:00

  • Social networks and risk of delayed hospital arrival after acute stroke.

    abstract::Arriving rapidly to the hospital after a heart attack or stroke is critical for patients to be within time windows for treatment. Prior research in heart attacks has suggested a paradoxical role of the social environment: those who arrive early are surrounded by nonrelatives, while those who arrive late are surrounded...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Dhand A,Luke D,Lang C,Tsiaklides M,Feske S,Lee JM

    更新日期:2019-03-14 00:00:00

  • Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis.

    abstract::Ductal occlusion has been postulated to precipitate focal pancreatic inflammation, while the nature of the primary occluding agents has remained elusive. Neutrophils make use of histone citrullination by peptidyl arginine deiminase-4 (PADI4) in contact to particulate agents to extrude decondensed chromatin as neutroph...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Leppkes M,Maueröder C,Hirth S,Nowecki S,Günther C,Billmeier U,Paulus S,Biermann M,Munoz LE,Hoffmann M,Wildner D,Croxford AL,Waisman A,Mowen K,Jenne DE,Krenn V,Mayerle J,Lerch MM,Schett G,Wirtz S,Neurath MF,Herrm

    更新日期:2016-03-11 00:00:00

  • Disease risk scores for skin cancers.

    abstract::We trained and validated risk prediction models for the three major types of skin cancer- basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma-on a cross-sectional and longitudinal dataset of 210,000 consented research participants who responded to an online survey covering personal and family histo...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Fontanillas P,Alipanahi B,Furlotte NA,Johnson M,Wilson CH,23andMe Research Team.,Pitts SJ,Gentleman R,Auton A

    更新日期:2021-01-08 00:00:00

  • Quasi-continuous transition from a Fermi liquid to a spin liquid in κ-(ET)2Cu2(CN)3.

    abstract::The Mott metal-insulator transition-a manifestation of Coulomb interactions among electrons-is known as a discontinuous transition. Recent theoretical studies, however, suggest that the transition is continuous if the Mott insulator carries a spin liquid with a spinon Fermi surface. Here, we demonstrate the case of a ...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Furukawa T,Kobashi K,Kurosaki Y,Miyagawa K,Kanoda K

    更新日期:2018-01-22 00:00:00

  • SREBP1 drives Keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ERα breast cancer.

    abstract::Approximately 30% of ERα breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epig...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Perone Y,Farrugia AJ,Rodríguez-Meira A,Győrffy B,Ion C,Uggetti A,Chronopoulos A,Marrazzo P,Faronato M,Shousha S,Davies C,Steel JH,Patel N,Del Rio Hernandez A,Coombes C,Pruneri G,Lim A,Calvo F,Magnani L

    更新日期:2019-05-09 00:00:00

  • Dynamic histone marks in the hippocampus and cortex facilitate memory consolidation.

    abstract::Memory consolidation requires a timely controlled interplay between the hippocampus, a brain region important for memory formation, and the cortex, a region recruited for memory storage. Here we show that memory consolidation is associated with specific epigenetic modifications on histone proteins that have a distinct...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Gräff J,Woldemichael BT,Berchtold D,Dewarrat G,Mansuy IM

    更新日期:2012-01-01 00:00:00

  • Allelic variation contributes to bacterial host specificity.

    abstract::Understanding the molecular parameters that regulate cross-species transmission and host adaptation of potential pathogens is crucial to control emerging infectious disease. Although microbial pathotype diversity is conventionally associated with gene gain or loss, the role of pathoadaptive nonsynonymous single-nucleo...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Yue M,Han X,De Masi L,Zhu C,Ma X,Zhang J,Wu R,Schmieder R,Kaushik RS,Fraser GP,Zhao S,McDermott PF,Weill FX,Mainil JG,Arze C,Fricke WF,Edwards RA,Brisson D,Zhang NR,Rankin SC,Schifferli DM

    更新日期:2015-10-30 00:00:00

  • Using controlled disorder to probe the interplay between charge order and superconductivity in NbSe2.

    abstract::The interplay between superconductivity and charge-density wave (CDW) in 2H-NbSe2 is not fully understood despite decades of study. Artificially introduced disorder can tip the delicate balance between two competing long-range orders, and reveal the underlying interactions that give rise to them. Here we introduce dis...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Cho K,Kończykowski M,Teknowijoyo S,Tanatar MA,Guss J,Gartin PB,Wilde JM,Kreyssig A,McQueeney RJ,Goldman AI,Mishra V,Hirschfeld PJ,Prozorov R

    更新日期:2018-07-18 00:00:00

  • Large Igneous Province thermogenic greenhouse gas flux could have initiated Paleocene-Eocene Thermal Maximum climate change.

    abstract::Large Igneous Provinces (LIPs) are associated with the largest climate perturbations in Earth's history. The North Atlantic Igneous Province (NAIP) and Paleocene-Eocene Thermal Maximum (PETM) constitute an exemplar of this association. As yet we have no means to reconstruct the pacing of LIP greenhouse gas emissions f...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Jones SM,Hoggett M,Greene SE,Dunkley Jones T

    更新日期:2019-12-05 00:00:00

  • High frequency neural spiking and auditory signaling by ultrafast red-shifted optogenetics.

    abstract::Optogenetics revolutionizes basic research in neuroscience and cell biology and bears potential for medical applications. We develop mutants leading to a unifying concept for the construction of various channelrhodopsins with fast closing kinetics. Due to different absorption maxima these channelrhodopsins allow fast ...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Mager T,Lopez de la Morena D,Senn V,Schlotte J,D Errico A,Feldbauer K,Wrobel C,Jung S,Bodensiek K,Rankovic V,Browne L,Huet A,Jüttner J,Wood PG,Letzkus JJ,Moser T,Bamberg E

    更新日期:2018-05-01 00:00:00

  • Adrenal hormones mediate disease tolerance in malaria.

    abstract::Malaria reduces host fitness and survival by pathogen-mediated damage and inflammation. Disease tolerance mechanisms counter these negative effects without decreasing pathogen load. Here, we demonstrate that in four different mouse models of malaria, adrenal hormones confer disease tolerance and protect against early ...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Vandermosten L,Pham TT,Knoops S,De Geest C,Lays N,Van der Molen K,Kenyon CJ,Verma M,Chapman KE,Schuit F,De Bosscher K,Opdenakker G,Van den Steen PE

    更新日期:2018-10-30 00:00:00

  • Inactivation of a CRF-dependent amygdalofugal pathway reverses addiction-like behaviors in alcohol-dependent rats.

    abstract::The activation of a neuronal ensemble in the central nucleus of the amygdala (CeA) during alcohol withdrawal has been hypothesized to induce high levels of alcohol drinking in dependent rats. In the present study we describe that the CeA neuronal ensemble that is activated by withdrawal from chronic alcohol exposure c...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: de Guglielmo G,Kallupi M,Pomrenze MB,Crawford E,Simpson S,Schweitzer P,Koob GF,Messing RO,George O

    更新日期:2019-03-18 00:00:00

  • A Ca(2+)-dependent signalling circuit regulates influenza A virus internalization and infection.

    abstract::Various viruses enter host cells via endocytosis, but the molecular mechanisms underlying the specific internalization pathways remain unclear. Here we show that influenza A viruses (IAVs) enter cells via redundant pathways of clathrin-mediated and clathrin-independent endocytosis, with intracellular Ca(2+) having a c...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Fujioka Y,Tsuda M,Nanbo A,Hattori T,Sasaki J,Sasaki T,Miyazaki T,Ohba Y

    更新日期:2013-01-01 00:00:00

  • Publisher Correction: Orbital bistatic radar observations of asteroid Vesta by the Dawn mission.

    abstract::An incorrect version of the Supplementary Information was inadvertently published with this Article. The HTML has now been updated to include the correct version of the Supplementary Information. ...

    journal_title:Nature communications

    pub_type: 杂志文章,已发布勘误


    authors: Palmer EM,Heggy E,Kofman W

    更新日期:2017-11-23 00:00:00

  • Backmapping triangulated surfaces to coarse-grained membrane models.

    abstract::Many biological processes involve large-scale changes in membrane shape. Computer simulations of these processes are challenging since they occur across a wide range of spatiotemporal scales that cannot be investigated in full by any single current simulation technique. A potential solution is to combine different lev...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Pezeshkian W,König M,Wassenaar TA,Marrink SJ

    更新日期:2020-05-08 00:00:00

  • Proteogenomic landscape of squamous cell lung cancer.

    abstract::How genomic and transcriptomic alterations affect the functional proteome in lung cancer is not fully understood. Here, we integrate DNA copy number, somatic mutations, RNA-sequencing, and expression proteomics in a cohort of 108 squamous cell lung cancer (SCC) patients. We identify three proteomic subtypes, two of wh...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Stewart PA,Welsh EA,Slebos RJC,Fang B,Izumi V,Chambers M,Zhang G,Cen L,Pettersson F,Zhang Y,Chen Z,Cheng CH,Thapa R,Thompson Z,Fellows KM,Francis JM,Saller JJ,Mesa T,Zhang C,Yoder S,DeNicola GM,Beg AA,Boyle TA

    更新日期:2019-08-08 00:00:00

  • NPM1 upregulates the transcription of PD-L1 and suppresses T cell activity in triple-negative breast cancer.

    abstract::Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) interaction plays a crucial role in tumor-associated immune escape. Here, we verify that triple-negative breast cancer (TNBC) has higher PD-L1 expression than other subtypes. We then discover that nucleophosmin (NPM1) binds to PD-L1 promoter...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Qin G,Wang X,Ye S,Li Y,Chen M,Wang S,Qin T,Zhang C,Li Y,Long Q,Hu H,Shi D,Li J,Zhang K,Zhai Q,Tang Y,Kang T,Lan P,Xie F,Lu J,Deng W

    更新日期:2020-04-03 00:00:00

  • Publisher Correction: A multistage rotational speed changing molecular rotor regulated by pH and metal cations.

    abstract::The original version of this Article omitted the Received and Accepted dates; they should have been 22nd January 2018 and 19th April 2018, respectively. This has been corrected in the PDF and HTML versions of the Article. ...

    journal_title:Nature communications

    pub_type: 杂志文章,已发布勘误


    authors: Wu Y,Wang G,Li Q,Xiang J,Jiang H,Wang Y

    更新日期:2018-06-13 00:00:00

  • Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability.

    abstract::In human cancers, oncogenic mutations commonly occur in the RAS genes KRAS, NRAS, or HRAS, but there are no clinical RAS inhibitors. Mutations are more prevalent in KRAS, possibly suggesting a unique oncogenic activity mediated by KRAS-specific interaction partners, which might be targeted. Here, we determine the spec...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Adhikari H,Counter CM

    更新日期:2018-09-07 00:00:00

  • Structural basis for Ca2+-dependent activation of a plant metacaspase.

    abstract::Plant metacaspases mediate programmed cell death in development, biotic and abiotic stresses, damage-induced immune response, and resistance to pathogen attack. Most metacaspases require Ca2+ for their activation and substrate processing. However, the Ca2+-dependent activation mechanism remains elusive. Here we report...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Zhu P,Yu XH,Wang C,Zhang Q,Liu W,McSweeney S,Shanklin J,Lam E,Liu Q

    更新日期:2020-05-07 00:00:00

  • Disclosing the temperature of columnar jointing in lavas.

    abstract::Columnar joints form by cracking during cooling-induced contraction of lava, allowing hydrothermal fluid circulation. A lack of direct observations of their formation has led to ambiguity about the temperature window of jointing and its impact on fluid flow. Here we develop a novel thermo-mechanical experiment to disc...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: Lamur A,Lavallée Y,Iddon FE,Hornby AJ,Kendrick JE,von Aulock FW,Wadsworth FB

    更新日期:2018-04-12 00:00:00

  • Plasmonic tunnel junctions for single-molecule redox chemistry.

    abstract::Nanoparticles attached just above a flat metallic surface can trap optical fields in the nanoscale gap. This enables local spectroscopy of a few molecules within each coupled plasmonic hotspot, with near thousand-fold enhancement of the incident fields. As a result of non-radiative relaxation pathways, the plasmons in...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: de Nijs B,Benz F,Barrow SJ,Sigle DO,Chikkaraddy R,Palma A,Carnegie C,Kamp M,Sundararaman R,Narang P,Scherman OA,Baumberg JJ

    更新日期:2017-10-20 00:00:00

  • Accounting for diverse evolutionary forces reveals mosaic patterns of selection on human preterm birth loci.

    abstract::Currently, there is no comprehensive framework to evaluate the evolutionary forces acting on genomic regions associated with human complex traits and contextualize the relationship between evolution and molecular function. Here, we develop an approach to test for signatures of diverse evolutionary forces on trait-asso...

    journal_title:Nature communications

    pub_type: 杂志文章


    authors: LaBella AL,Abraham A,Pichkar Y,Fong SL,Zhang G,Muglia LJ,Abbot P,Rokas A,Capra JA

    更新日期:2020-07-24 00:00:00