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1. Danilchanka, Olga V. Diffusion pathways through the outer membrane of mycobacteria.
Degree: PhD, 2009, University of Alabama – Birmingham
The extraordinary capacity of Mycobacterium tuberculosis (Mtb) to adapt to environmental changes during infection contributes to its success as a pathogen. While the unique outer membrane (OM) of mycobacteria functions as a permeability barrier for toxic molecules, uptake of nutrients is required to sustain viability of Mtb. Whereas hydrophobic molecules can diffuse through membranes, uptake of small hydrophilic compounds is mediated by water-filled channels, porins. For example, Msp-like porins of M. smegmatis (Ms) were shown to be required for uptake of hydrophilic β-lactam antibiotics, which are also known to diffuse through porins in gram-negative bacteria. Because the structure of the OM of Ms and Mtb is similar, we hypothesized that disruption of an unknown porin in Mtb would increase resistance to β-lactams. A transposon library of M. bovis BCG (BCG) was screened for mutants with increased resistance to ampicillin. Mutations were found in genes required for the biosynthesis of the OM as well as two previously uncharacterized genes, rv0194 and rv3903c. Overexpression of rv0194 in BCG and Ms showed that Rv0194 functions as an ATP-binding cassette efflux pump that confers resistance to β-lactams, suggesting that Mtb has tripartite drug efflux pumps that span the entire cell envelope similar to that of E. coli. A mutation in rv3903c largely increased resistance to hydrophilic drugs and conferred resistance to nitric oxide both in vitro and in vivo. Uptake of glycerol was minimal in the rv3903c mutant resulting in decreased growth rate, which can be restored when grown on medium with the hydrophobic nutrient, oleic acid, as the sole carbon source. The recombinant N-terminal domain of Rv3903c purified from Ms and E. coli had a channel activity with a primary single conductance of 4.0±0.2 nS. Furthermore, it was able to complement the growth defect of the rv3903c mutant and an msp porin mutant of Ms. We suggest that Rv3903c is the first identified porin of Mtb in a new class of proteins with an unusual signal sequence and unique domain organization. Taken together, this work significantly advances our understanding of the transport mechanisms for nutrients and toxic compounds in mycobacteria.
1 online resource (ix, 145 p.) : ill., digital, PDF file.
Joint Health Sciences
UNRESTRICTEDAdvisors/Committee Members: Niederweis, Michael, Bedwell, David M.<br>, Benjamin, William H.<br>, Dybvig, Kevin F.<br>, Stejn, Andries J.<br>, Turnbough, Charles L..
Subjects/Keywords: Anti-Bacterial Agents – metabolism<; br>; Bacterial Proteins – metabolism<; br>; Chloramphenicol – metabolism<; br>; Fluoroquinolones – metabolism<; br>; Membrane Transport Proteins – metabolism<; br>; Mycobacterium smegmatis<; br>; Mycobacterium tuberculosis – metabolism<; br>; Porins – metabolism
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APA (6th Edition):
Danilchanka, O. V. (2009). Diffusion pathways through the outer membrane of mycobacteria. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,1150
Chicago Manual of Style (16th Edition):
Danilchanka, Olga V. “Diffusion pathways through the outer membrane of mycobacteria.” 2009. Doctoral Dissertation, University of Alabama – Birmingham. Accessed December 12, 2019. http://contentdm.mhsl.uab.edu/u?/etd,1150.
MLA Handbook (7th Edition):
Danilchanka, Olga V. “Diffusion pathways through the outer membrane of mycobacteria.” 2009. Web. 12 Dec 2019.
Danilchanka OV. Diffusion pathways through the outer membrane of mycobacteria. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2009. [cited 2019 Dec 12]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,1150.
Council of Science Editors:
Danilchanka OV. Diffusion pathways through the outer membrane of mycobacteria. [Doctoral Dissertation]. University of Alabama – Birmingham; 2009. Available from: http://contentdm.mhsl.uab.edu/u?/etd,1150