Interaction of oligodeoxynucleotides with mycobacteria: implications for new therapeutic strategies.
The use of synthetic oligonucleotides (ONs) to systematically address new pharmacologic targets in mycobacteria would enhance the introduction of new molecular targets for drug intervention. Oligonucleotides' mechanism of action allows researchers to pursue the importance of particular proteins without the requirement of having purified samples. For this approach to be effective, mycobacteria must be able to transport ONs to their cytoplasm, and if this is not the case, the agents must be otherwise delivered. In this report, we characterize the ability of phosphorothioate (PS) and phosphorodiester (PD) ONs to interact with both Mycobacterium smegmatis and Mycobacterium tuberculosis. In addition, the use of delivery enhancer compounds, ethambutol and PAMAM dendrimer, was evaluated on the ON-mycobacteria interaction. ON interaction was demonstrated to be concentration-dependent, suggesting a possibly active component of the oligonucleotide and bacteria interaction. ON interaction could be increased by the coincubation of the bacteria with the delivery adjuvants. Treatment with ethambutol or dendrimers (fourth generation) was demonstrated to increase ON interaction with both species of mycobacteria although not to the same extent. The results of these preliminary experiments indicate that through use of the proper delivery adjuvant, ON interactions with mycobacteria can be increased. These findings may have implications for probing future antimycobacterial therapeutic targets.
Department of Pharmaceutics, University of Florida, Gainesville 32610, USA.
S A
SA
Attia
V E
VE
Shepherd
M N
MN
Rosenblatt
M K
MK
Davidson
J A
JA
Hughes
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004977:Ethambutol / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009161:Mycobacterium / Q000187:drug effects*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D009838:Oligodeoxyribonucleotides; D004977:Ethambutol