Metabolites, substrates and substrate impurities may be toxic to cells by damaging biological molecules, organelles, membranes or disrupting biological processes. Chemical stress is routinely encountered in bioprocessing to produce chemicals or fuels from renewable substrates, in whole-cell biocatalysis and bioremediation. Cells respond, adapt and may develop tolerance to chemicals by mechanisms only partially explored, especially for multiple simultaneous stresses. More is known about how cells respond to chemicals, but less about how to develop tolerant strains. Aiming to stimulate new metabolic engineering and synthetic-biology approaches for tolerant-strain development, this review takes a holistic, comparative and modular approach in bringing together the large literature on genes, programs, mechanisms, processes and molecules involved in chemical stress or imparting tolerance. These include stress proteins and transcription factors, efflux pumps, altered membrane composition, stress-adapted energy metabolism, chemical detoxification, and accumulation of small-molecule chaperons and compatible solutes. The modular organization (by chemicals, mechanism, organism, and methods used) imparts flexibility in exploring this complex literature, while comparative analyses point to hidden commonalities, such as an oxidative stress response underlying some solvent and carboxylic-acid stress. Successes involving one or a few genes, as well as global genomic approaches are reviewed with an eye to future developments that would engage novel genomic and systems-biology tools to create altered or semi-synthetic strains with superior tolerance characteristics for bioprocessing.
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