Abstract
Environmental factors like temperature, pressure, and pH partly shaped the evolution of life. As life progressed, new stressors (e.g., poisons and antibiotics) arose as part of an arms race among organisms. Here we ask if cells co-opted existing mechanisms to respond to new stressors, or whether new responses evolved de novo. We use a network-clustering approach based purely on phenotypic growth measurements and interactions among the effects of stressors on population growth. We apply this method to two types of stressors—temperature and antibiotics—to discover the extent to which their cellular responses overlap in Escherichia coli. Our clustering reveals that responses to low and high temperatures are clearly separated, and each is grouped with responses to antibiotics that have similar effects to cold or heat, respectively. As further support, we use a library of transcriptional fluorescent reporters to confirm heat-shock and cold-shock genes are induced by antibiotics. We also show strains evolved at high temperatures are more sensitive to antibiotics that mimic the effects of cold. Taken together, our results strongly suggest that temperature stress responses have been co-opted to deal with antibiotic stress.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Hoffmann AA, Parsons PA. Evolutionary genetics and environmental stress. Oxford, England, UK: Oxford University Press; 1991.
Meyers LA, Bull JJ. Fighting change with change: adaptive variation in an uncertain world. Trends Ecol Evol. 2002;17:551–7.
Cho H, Uehara T, Bernhardt TG. Beta-lactam antibiotics induce a lethal malfunctioning of the bacterial cell wall synthesis machinery. Cell. 2014;159:1300–11.
Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, Collins JJ. A common mechanism of cellular death induced by bactericidal antibiotics. Cell. 2007;130:797–810.
Gilchrist GW. Specialists and generalists in changing environments. I. Fitness landscapes of thermal sensitivity. Am Nat. 1995;146:252–70.
Csonka LN, Hanson AD. Prokaryotic osmoregulation: genetics and physiology. Annu Rev Microbiol. 1991;45:569–606.
Sharma UK, Chatterji D. Transcriptional switching in Escherichia coli during stress and starvation by modulation of σ70 activity. FEMS Microbiol Rev. 2010;34:646–57.
Levy SB. Active efflux mechanisms for antimicrobial resistance. Antimicrob Agents Chemother. 1992;36:695.
Paulsen IT, Park JH, Choi PS, Saier MH Jr. A family of gram-negative bacterial outer membrane factors that function in the export of proteins, carbohydrates, drugs and heavy metals from gram-negative bacteria. FEMS Microbiol Lett. 1997;156:1–8.
Begic S, Worobec EA. Regulation of Serratia marcescens ompF and ompC porin genes in response to osmotic stress, salicylate, temperature and pH. Microbiology. 2006;152:485–91.
Kaprelyants AS, Kell DB. Dormancy in stationary-phase cultures of Micrococcus luteus: flow cytometric analysis of starvation and resuscitation. Appl Environ Microbiol. 1993;59:3187–96.
Bada JL, Lazcano A. Some like it hot, but not the first biomolecules. Science. 2002;296:1982–3.
Braun D, Libchaber A. Thermal force approach to molecular evolution. Phys Biol. 2004;1:P1.
Daniel I, Oger P, Winter R. Origins of life and biochemistry under high-pressure conditions. Chem Soc Rev. 2006;35:858–75.
Hazen RM, Boctor N, Brandes JA, Cody GD, Hemley RJ, Sharma A, et al. High pressure and the origin of life. J Phys Condens Matter. 2002;14:11489.
Schwartzman DW, Lineweaver CH. The hyperthermophilic origin of life revisited. Biochemical Society Transactions. 2004;32(2):168-71.
Stetter KO. Hyperthermophiles in the history of life. Philos Trans R Soc Lond B Biol Sci. 2006;361:1837–43.
Åkerfelt M, Morimoto RI, Sistonen L. Heat shock factors: integrators of cell stress, development and lifespan. Nat Rev Mol Cell Biol. 2010;11:545.
De AM. Heat shock proteins: facts, thoughts, and dreams. Shock. 1999;11:1–12.
Lindquist S. The heat-shock response. Annu Rev Biochem. 1986;55:1151–91.
Richter K, Haslbeck M, Buchner J. The heat shock response: life on the verge of death. Mol Cell. 2010;40:253–66.
D’Costa VM, King CE, Kalan L, Morar M, Sung WW, Schwarz C, et al. Antibiotic resistance is ancient. Nature. 2011;477:457.
Mondal S, Pathak BK, Ray S, Barat C. Impact of P-Site tRNA and antibiotics on ribosome mediated protein folding: studies using the Escherichia coli ribosome. PLoS ONE. 2014;9:e101293.
Vabulas RM, Raychaudhuri S, Hayer-Hartl M, Hartl FU. Protein folding in the cytoplasm and the heat shock response. Cold Spring Harb Perspect Biol. 2010;2:a004390.
Dragosits M, Mozhayskiy V, Quinones‐Soto S, Park J, Tagkopoulos I. Evolutionary potential, cross‐stress behavior and the genetic basis of acquired stress resistance in Escherichia coli. Mol Syst Biol. 2013;9:643.
Święciło A. Cross-stress resistance in Saccharomyces cerevisiae yeast—new insight into an old phenomenon. Cell Stress Chaperones. 2016;21:187–200.
Völker U, Mach H, Schmid R, Hecker M. Stress proteins and cross-protection by heat shock and salt stress in Bacillus subtilis. Microbiology. 1992;138:2125–35.
Battesti A, Majdalani N, Gottesman S. The RpoS-mediated general stress response in Escherichia coli. Annu Rev Microbiol. 2011;65:189–213.
Gruber TM, Gross CA. Multiple sigma subunits and the partitioning of bacterial transcription space. Annu Rev Microbiol. 2003;57:441–66.
Somorin Y, Abram F, Brennan F, O’Byrne C. The general stress response is conserved in long-term soil-persistent strains of Escherichia coli. Appl Environ Microbiol. 2016;82:4628–40.
Cardoso K, Gandra RF, Wisniewski ES, Osaku CA, Kadowaki MK, Felipach-Neto V, et al. DnaK and GroEL are induced in response to antibiotic and heat shock in Acinetobacter baumannii. J Med Microbiol. 2010;59:1061–8.
Loughman K, Hall J, Knowlton S, Sindeldecker D, Gilson T, Schmitt DM, et al. Temperature-dependent gentamicin resistance of Francisella tularensis is mediated by uptake modulation. Front Microbiol. 2016;7:37.
Rodríguez-Verdugo A, Gaut BS, Tenaillon O. Evolution of Escherichia coli rifampicin resistance in an antibiotic-free environment during thermal stress. BMC Evol Biol. 2013;13:50.
Goltermann L, Good L, Bentin T. Chaperonins fight aminoglycoside-induced protein misfolding and promote short-term tolerance in Escherichia coli. J Biol Chem. 2013;288:10483–9.
Poole K. Stress responses as determinants of antimicrobial resistance in Gram-negative bacteria. Trends Microbiol. 2012;20:227–34.
Segre D, DeLuna A, Church GM, Kishony R. Modular epistasis in yeast metabolism. Nat Genet. 2005;37:77.
Yeh P, Tschumi AI, Kishony R. Functional classification of drugs by properties of their pairwise interactions. Nat Genet. 2006;38:489.
Bliss C. The toxicity of poisons applied jointly. Ann Appl Biol. 1939;26:585–615.
Datsenko KA, Wanner BL. One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc Natl Acad Sci USA. 2000;97:6640–5.
Zaslaver A, Bren A, Ronen M, Itzkovitz S, Kikoin I, Shavit S, et al. A comprehensive library of fluorescent transcriptional reporters for Escherichia coli. Nat Methods. 2006;3:623.
Reyes VC, Li M, Hoek EM, Mahendra S, Damoiseaux R. Genome-wide assessment in Escherichia coli reveals time-dependent nanotoxicity paradigms. ACS Nano. 2012;6:9402–15.
Mingeot-Leclercq M-P, Glupczynski Y, Tulkens PM. Aminoglycosides: activity and resistance. Antimicrob Agents Chemother. 1999;43:727–37.
Chopra I, Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev. 2001;65:232–60.
Yamanaka K. Cold shock response in Escherichia coli. J Mol Microbiol Biotechnol. 1999;1:193–202.
Goldstein E, Drlica K. Regulation of bacterial DNA supercoiling: plasmid linking numbers vary with growth temperature. Proc Natl Acad Sci USA. 1984;81:4046–50.
Mizushima T, Kataoka K, Ogata Y, Inoue R, Sekimizu K. Increase in negative supercoiling of plasmid DNA in Escherichia coli exposed to cold shock. Mol Microbiol. 1997;23:381–6.
Niu P, Liu L, Gong Z, Tan H, Wang F, Yuan J, et al. Overexpressed heat shock protein 70 protects cells against DNA damage caused by ultraviolet C in a dose-dependent manner. Cell Stress Chaperones. 2006;11:162–9.
VanBogelen RA, Neidhardt FC. Ribosomes as sensors of heat and cold shock in Escherichia coli. Proc Natl Acad Sci USA. 1990;87:5589–93.
Bhatti A, Kumar K, Stobo C, Chaudhry G, Ingram J. High temperature induced antibiotic sensitivity changes in Pseudomonas aeruginosa. Microbios. 1999;97:103–15.
Wang N, Yamanaka K, Inouye M. CspI, the ninth member of the CspA family of Escherichia coli, is induced upon cold shock. J Bacteriol. 1999;181:1603–9.
Acknowledgements
We are grateful for funding from the Hellman Foundation (P.J.Y.), a KL2 Fellowship (P.J.Y.) through the NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001881, and a James F. McDonnell Foundation Complex Systems Scholar Award (V.M.S.). Author M.C.-L. is supported by UC-MEXUS and CONACYT. The high-temperature-adapted strains used in this paper were kindly donated by Alejandra Rodríguez-Verdugo, Brandon Gaut, and collaborators (Rodríguez-Verdugo et al., 2013).
Disclaimer
This investigation was supported by NIH, under Ruth L. Kirschstein National Research Service Award (T32-GM008185). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Author contributions
Conceptualization: M.C.-L., T.M.K., V.M.S. and P.J.Y.; experimental work: T.M.K., R.W., N.A.L. and R.D.; computational work and data analysis: M.C.-L.; theoretical development: M.C.-L., E.T., V.M.S. and P.J.Y; writing: M.C.-L., T.M.K., N.A.L., V.M.S. and P.J.Y.; supervision: V.M.S. and P.J.Y.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Cruz-Loya, M., Kang, T.M., Lozano, N.A. et al. Stressor interaction networks suggest antibiotic resistance co-opted from stress responses to temperature. ISME J 13, 12–23 (2019). https://doi.org/10.1038/s41396-018-0241-7
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41396-018-0241-7
This article is cited by
-
Climate change and antimicrobial resistance: a global-scale analysis
BMC Infectious Diseases (2025)
-
One Health, One Microbiome
Microbiome (2025)
-
The silent microbial shift: climate change amplifies pathogen evolution, microbiome dysbiosis, and antimicrobial resistance
Tropical Diseases, Travel Medicine and Vaccines (2025)
-
Altered gene expression of cold shock proteins under antibiotic exposure
The Journal of Antibiotics (2025)
-
Metagenomic co-assembly uncovers mobile antibiotic resistance genes in airborne microbiomes
Communications Earth & Environment (2025)
