Mills Laboratory > Research > Genomics and Applied Genetics of Fermentation-Related Bacteria

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Genomics and Applied Genetics of Fermentation-Related Bacteria

Block lab fermentorsOverview

Lactc acid bacteria (LAB) are involved in numerous food and beverage fermentations. We are interested in the fundamental biology of this group of organisms as they are applied in various "working" environments.


Engineering heterologous protein production in Lactococcus lactis.

Engineered LAB are increasingly used to deliver therapeutic proteins to the gastrointestinal tract.   We have an ongoing interest in molecular strategies to exploit the food grade bacterium, Lactococcus lactis, for the oral delivery of therapeutic or prophylactic proteins.  We are developing novel tools to overexpress proteins in L. lactis and exploring the impact of that expression on the lactococcal responses.  A general goal of this focus is to identify the biological mechanisms that limit protein expression.


oddoneplasmidsBiology of LAB involved in biofuel fermentations.

LAB are often involved in biofuel fermentations both as spoilage agents and as novel catalysts for new approaches for fuel and chemical production.   We are interested in understanding the fundamental mechanisms that allow some LAB to resist ethanol and other inhibitors associated with lignocellulosic fermentations.


Some questions about LAB we are interested in:

  • What genes/regulons limit protein overproduction inside L. lactis?
  • Does increasing antigen production in L. lactis increase oral vaccine effectiveness?
  • Can media development/optimization increase protein production per cell in L. lactis?
  • Can a metabolic model accurately identify genes that impact protein production by L. lactis?
  • What are the genes in LAB that endow resistance to ethanol and other plant-based inhibitors?
  • How is sugar consumption regulated in obligately herterofermentative LAB?


Publications in this area (see a full list of Mills Lab publications here)

  • Jeong KH, B. Israr, S. P. Shoemaker, D. A. Mills, J. Kim. 2016.  Impact of lactic acid and hydrogen ion on the simultaneous fermentation of glucose and xylose by the carbon catabolite derepressed Lactobacillus brevis ATCC 14869.  Journal of Microbiology and Biotechnology (In Press).
  • Kim, S. R., T. V. Nguyen, N. R. Seo, S. Jung, H. J. An, D. A. Mills, and J.-H. Kim. 2015. Comparative proteomics: assessment of biological variability and dataset comparability.  BMC Bioinformatics. 16:121.
  • Liu S., T. D. Leathers, A. Copeland, O. Chertkov, L. Goodwin, and D. A. Mills. 2011. Genome sequence of Lactobacillus buchneri NRRL B-30929, a novel strain from a commercial ethanol plant.  Journal of Bacteriology 193:4019-4020. (July issue cover).
  • Kim, J-H.  D. E. Block and D. A. Mills.  2010. Simultaneous consumption of pentose and hexose sugars: An optimal microbial phenotype for efficient fermentation of lignocellulosic biomass. Applied Microbiology and Biotechnology 88:1077-1085.
  • Kim, J-H.  D. E. Block, S. P. Shoemaker and D. A. Mills.  2010. Atypical ethanol production by carbon catabolite derepressed lactobacilli. BioResource Technology 101:8790-8797.
  • Kim, J-H. D. E. Block, S. P. Shoemaker and D. A. Mills.  Conversion of rice straw to bio-based chemicals: an integrated process using Lactobacillus brevis.  Applied Microbiology and Biotechnology 86:1375-1385.
  • Oddone, G. M., D. A. Mills and D. E. Block. 2009. A dynamic, genome-scale flux model of Lactococcus lactis to increase specific recombinant protein expression.  Metabolic Engineering 11:367-381.
  • Oddone, G. M., D. A. Mills and D. E. Block. 2009.  Dual inducible expression of recombinant GFP and targeted antisense RNA in Lactococcus lactis.  Plasmid 62:108:118.
  • Oddone, G. M, D. A. Mills and D. E. Block. 2009. Incorporation of nisI-mediated nisin immunity improves vector-based nisin-controlled gene expression in lactic acid bacteria.  Plasmid 61:151-158.
  • Kim, J.-H., S. Shoemaker, and D. A. Mills. 2009. Relaxed control of sugar utilization in Lactobacillus brevis. Microbiology 155: 1351-1359.
  • Zhang, G., D. A. Mills and D. E. Block. 2009. Development and optimization of chemically-defined media supporting high cell density growth of lactococci, enterococci, and streptococci.  Applied and Environmental Microbiology 75:1080-1087.
  • Sela, D, H. Rawsthorne and D. A. Mills. 2007. Characterization of the lactococcal group II intron target site in its native host.  Plasmid. 58:127-139.
  • Kim, J.-H. and D. A. Mills. 2007. Improvement of a nisin inducible expression vector for expression of heterologous genes in the lactic acid bacteria.  Plasmid. 58:275-283.
  • Oddone, G. M., Q. Q. Lan, H. Rawsthorne, D. A. Mills, and D. E. Block. 2006. Optimization of fed batch production of the model recombinant protein GFP in Lactococcus lactis. Biotechnology and Bioengineering. 96:1127-1138.
  • Lan, C., G. Oddone, D. A. Mills, and D. E. Block. Kinetics of Lactococcus lactis growth and metabolite formation under aerobic and anaerobic conditions at the presence or absence of hemin. 2006. Biotechnology and Bioengineering. 95:1070-1080.
  • Makarova, K., A. Slesarev, Y. Wolf, A. Sorokin, B. Mirkin, E. Koonin, A. Pavlov, N. Pavlova, V. Karamychev, N. Polouchine, V. Shakhova, I. Grigoriev, Y. Lou, D. Rohksar, S. Lucas, K. Huang, D. M. Goodstein, T. Hawkins, V. Plengvidhya, D. Welker, J. Hughes, Y. Goh, A. Benson, K. Baldwin, J.-H. Lee, I. Díaz-Muñiz, B. Dosti, V. Smeianov, W. Wechter, R. Barabote, G. Lorca, E. Altermann, R. Barrangou, B. Ganesan, Y. Xie, H. Rawsthorne, D. Tamir, C. Parker, L. McKay, F. Breidt, J. Broadbent, R. Hutkins, D. O’Sullivan, J. Steele, G. Unlu, M. Saier, T. Klaenhammer, P. Richardson, S. Kozyavkin, B. Weimer, and D. A. Mills. 2006. Comparative genomics of the lactic acid bacteria. 2006. Proceedings of the National Academy of Sciences. 103:15611-15616.
  • Rawsthorne, H, K. N. Turner, and D. A. Mills. 2006. Multicopy integration of heterologous genes using the lactococcal group II intron targeted to bacterial insertion sequences. Applied and Environmental Microbiology. 72:6088-6093.
  • LoCascio, R., D. A. Mills, A. L. Waterhouse. 2006. Reduction of catechin, rutin and quercetin levels by interaction with food-related microorganisms in a resting state. Journal of the Science of Food and Agriculture. 86:2105-2112.
  • Mills, D. A. 2004. The lactic acid bacteria genome project. Journal of Food Science, 69: FMS28-30.
  • Frazier, C. J. SanFillipo, A. Lambowitz and D. A. Mills. 2003. Genetic manipulation of Lactococcus lactis using targeted group II introns: generation of stable insertions without selection. Applied and Environmental Microbiology 69:1121-1128.
  • Klaenhammer, T, E. Altermann, F. Arigoni, A. Bolotin, F. Breidt, J. Broadbent, R. Cano, S. Chaillou, J. Deutscher, M. Gasson, M. van de Guchte, J. Guzzo, T. Hawkins, P. Hols, R. Hutkins, M. Kleerebezem, J. Kok, O. Kuipers, M. Lubbers, E. Maguin, L. McKay, D. A. Mills, A. Nauta, R. Overbeek, H. Pel, D. Pridmore, M. Saier, D. van Sinderen, A. Sorokin, J. Steele, D. O'Sullivan, W. de Vos, B. Weimer, M. Zagorec, and R. Siezen. Discovering lactic acid bacteria by genomics. 2002. Antonie van Leeuwenhoek 82:29-58.
  • Mills, D. A. 2001. Mutagenesis in the post genomics era: Tools for generating insertional mutations in the Lactic Acid Bacteria. Current Opinion in Biotechnology 12:503-509.


This work has received funding from:

Department of Energy

California Dairy Research Foundation

American Vineyard Foundation

California Competitive Grants Program for Research in Viticulture and Enology


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