Investigators and Program Directors
Harry W. Taber
Research Scientist, Wadsworth Center, Mycobacterial Disease
Professor, School of Public Health, Biomedical Sciences
Ph.D., University of Rochester School of Medicine
Postdoctoral training, University of Rochester, NIH, and
Gif-sur-Yvette
Research Interests
Among pathogenic bacteria, resistance to antimicrobial agents can arise by three distinct mechanisms:
- mutational alteration in target molecules,
- acquisition of new genes that modify targets or inactive antibiotics, or
- changes in antibiotic concentrations inside the bacteria cell.
The last of these can occur either by decreased uptake of antibiotic, or by efflux of antibiotic from the cell. Our laboratory is studying transcriptional regulation of bacterial bioenergetic systems as a mechanism for modulating antibiotic uptake and hence the level of antibiotic resistance exhibited under varying physiological conditions. Two experimental systems are being examined: first, the ctaBCDEF operon of Bacillus subtilis encoding the terminal oxidase cytochrome caa3, which we have established is essential for aminoglycoside antibiotic uptake by this organism. This operon is subject to "differential catabolite repression", which affects only the distal four genes and appears to function by a termination/ antitermination mechanism. This mechanism and its effect on drug resistance are under active study. The second system is comprised of the nar genes in Mycrobacterium smegmatis, an organism that serves as a surrogate for Mycobacterium tuberculosis. The nar genes encode nitrate reductase and its transcriptional regulators. Nitrate is used by mycrobacteria in place of oxygen as a terminal electron acceptor under anaerobic conditions. We have cloned the narL regulator gene of M. smegmatis and are studying its place in the transcriptional regulatory circuit controlling the nitrate reductase structural genes. This regulation is being correlated with changes in drug susceptibility of mycobacteria under anaerobic conditions, conditions that are known in other bacteria to markedly decrease drug uptake and compromise susceptibility. These results have applications to drug therapy and drug susceptibility testing of M. tuberculosis.
Contact Information
E-mail: taber@wadsworth.org.