Hiroshi Nikaido
University of California, Berkeley
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Primary Section: 44, Microbial Biology Secondary Section: 21, Biochemistry Membership Type:
Emeritus
(elected 2009)
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Research Interests
As a microbiologist, I have always been fascinated by the observation that gram-negative bacteria (such as E. coli) are intrinsically more resistant to a number of toxic agents, such as antibiotics, biocides, and detergents, than gram-positive bacteria (such as pneumococcus). This interest led to the notion that the extra membrane layer that is present only in the gram-negatives, the outer membrane, serves as an effective permeability barrier. Pursuing the molecular basis of this barrier led to the study of lipopolysaccharides, a unique component of the outer membrane. We found that they are present in the outer membrane bilayer exclusively in the outer leaflet, the asymmetric construction giving rise to the unusually low permeability of this bilayer to lipophilic agents. Studies in a similar direction also led to the discovery of porins, which function as a molecular sieve, preventing the influx of large or lipophilic agents. However, the observed resistance levels to many antibiotics cannot be fully explained by the low permeability of the outer membrane alone. Our more recent studies showed that gram-negative bacteria usually express multidrug efflux pumps of very wide specificity and that these active pumps work synergistically with the passive permeability barrier of the outer membrane. Our recent efforts are focused on the elucidation of the mechanism of action of these pumps.
