Graeme L. Conn, PhD
Department of Biochemistry
Phone: (404) 727-5965
We use biochemical, biophysical and microbiological methods to study the activities, interactions and macromolecular structures of protein and RNA molecules involved in bacterial resistance to antibiotics and in the regulation of the human innate immune response.
Ribosomal RNA modification and antibiotic resistance in bacteria. The bacterial ribosome is the target for many clinically important antibiotics. The aminoglycosides, for example, typically bind the bacterial small (30S) ribosomal subunit in a region known as the “decoding center” and thereby induce errors in reading of the mRNA by the ribosome. Aminoglycoside-producing bacteria avoid self-intoxication by expressing 16S rRNA methyltransferase enzymes that site-specifically chemically modify the drug binding site and block aminoglycoside binding. While clinical resistance aminoglycosides has predominantly arisen through the action of drug modifying enzymes, the aminoglycoside-resistance 16S rRNA methyltransferases have more recently emerged as a major new threat to the continued efficacy of aminoglycosides (including the latest generation drugs). Of particular concern is the increasing world-wide identification of the aminoglycoside-resistance 16S rRNA methyltransferases within mobile genetic elements, often in combination with other resistance determinants, and within serious human pathogens (including four of six members of the “ESKAPE” group).
In collaboration with Dr. Christine Dunham’s group, our overall goals in this work are to determine the structures of these enzymes and their complexes with target molecules (cosubstrate SAM and 30S subunit), in order to dissect their substrate recognition and catalytic mechanisms. Ultimately, our results will provide a platform for development of specific inhibitors of these enzymes or novel antibiotics resistant to their effects.
Regulation of proteins of the innate immune system by cellular and viral non-coding RNAs. Proteins of the cellular innate immune system must accurately detect and distinguish foreign from self molecules in order to exert their protective effects. A potent pathogen-associated molecular pattern (PAMP) is cytosolic double-stranded RNA (dsRNA). dsRNA is detected by a group of cellular proteins with distinct but overlapping RNA molecular requirements for their activation. We have long-standing interests in understanding the molecular mechanisms that underpin the viral and cellular non-coding RNA-mediated regulation of two of these proteins: dsRNA-activated protein kinase (PKR) and the 2’-5’-oligoadenylate synthetase. We are examining the structures and interactions of these human protein with both inhibitory and activating non-coding RNAs s, to understand how they exert their regulatory effects. Such understanding is important to underpin development of novel host-targeted strategies to control infection.
- View publications on PubMed