The overall objective of this research is to understand the mechanisms involved in the expression and dissemination of genes responsible for antibiotic resistance in bacteria. During the five year continuation period covered by this application, increased emphasis will be placed on studying the molecular biology of Streptomyces, a bacterial genus that has evolved capabilities for the synthesis of multiple antibiotics, diverse resistance mechanisms to avoid self-destruction by the antimicrobials produced, mechanisms for the formation of extra-chromosomal elements by excision of chromosomal DNA segments, and methods for highly efficient transfer of plasmids that carry antibiotic resistance determinants and other genetic traits. The relative paucity of information currently available about the molecular biology of Streptomyces contrasts sharply with the important biological role of these organisms with regard to the ecology of both antibiotic production and resistance, and their value as a model system for study of developmentally regulated control of gene expression.
The specific aims of the work include: [1] characterization of the molecular nature and functional activity of the signals involved in regulating gene expression in Streptomyces, [2] identification of Streptomyces genes and mechanisms that accomplish the developmentally-coordinated control of antibiotic production, antibiotic resistance, and morphological differentiation, [3] elucidation of the mechanisms by which gene transfer occurs in Streptomyces, and [4] study of the recombinational processes by which Streptomyces can acquire new synthetic capabilities by the chromosomal integration of exogenously derived genes, and by which segments of Streptomyces chromosomal DNA can excise to form autonomously replicating and self-transmissible plasmids. The proposed multi-faceted study is based on the rationale that an understanding of fundamental mechanisms controlling the genesis, expression and dissemination of genes for the synthesis of, and resistance to, antibiotics in microorganisms is of central importance to the eventual control of antimicrobial resistance in medically important pathogenic bacteria. Such fundamental information may also eventually enable the rational modification of antimicrobial agents to circumvent resistance mechanisms.
| Tamura, Masaru; Moore, Christopher J; Cohen, Stanley N (2013) Nutrient dependence of RNase E essentiality in Escherichia coli. J Bacteriol 195:1133-41 |
| Manasherob, Robert; Miller, Christine; Kim, Kwang-sun et al. (2012) Ribonuclease E modulation of the bacterial SOS response. PLoS One 7:e38426 |
| Tamura, Masaru; Kers, Johan A; Cohen, Stanley N (2012) Second-site suppression of RNase E essentiality by mutation of the deaD RNA helicase in Escherichia coli. J Bacteriol 194:1919-26 |
| Go, Hayoung; Moore, Christopher J; Lee, Minho et al. (2011) Upregulation of RNase E activity by mutation of a site that uncompetitively interferes with RNA binding. RNA Biol 8:1022-34 |
| Xu, Weijing; Huang, Jianqiang; Lin, Richard et al. (2010) Regulation of morphological differentiation in S. coelicolor by RNase III (AbsB) cleavage of mRNA encoding the AdpA transcription factor. Mol Microbiol 75:781-91 |
