Microbiologist
Emerging and Infectious Diseases
Southern Research Institute
2000 Ninth Avenue South
Birmingham, AL 35205
205-581-2558
E-mail: suling@sri.org
Dr. Suling graduated from Manhattan College and Duquesne University with B.S. and M.S. degrees in biology and microbiology, respectively. He then joined the Sloan-Kettering Institute for Cancer Research where he worked for five years participating in the investigation of folate metabolism in wild type and antifolate-resistant mutants of Entercococcus (Streptococcus) faecalis. Dr. Suling completed his graduate work at Cornell University Medical College under an NIH pre-doctoral fellowship and was awarded a Ph.D. in microbiology. His thesis work involved an investigation of the role of membrane lipids in antibiotic resistance in the Enterobacteriaceae. Prior to joining Southern Research in 1975, he studied diphtheria toxin production and the detoxification of purified toxin at the State Laboratory Institute, Massachusetts Department of Public Health. While at Southern Research, Dr. Suling has participated or acted as PI on government grants and contracts involving the metabolism and disposition of anticancer drugs, and on commercial contracts involving environmental microbiology and disinfection. Over the past12 years, his research interests have been in antimicrobial agents and chemotherapy of infections caused by Mycobacterium tuberculosis and Mycobacterium avium.
Effective chemotherapy of persons with AIDS who are also infected with M. tuberculosis or M. avium, especially multidrug-resistant MTB, can be difficult. Although some success has been achieved through the rational use of multiple drug combination therapy, the resistant nature of clinical isolates of M. avium and the appearance of drug-resistant M. tuberculosis emphasizes the need for new drugs to treat these infections. To address this need, my laboratory collaborates with scientists at Southern Research and elsewhere toward developing new drugs whose targets are cell envelope biosynthesis, cell division, or enzymes in the folate biosynthetic pathway.
The cell envelope composition of mycobacteria is unique in many ways, making it an attractive target for chemotherapy. Working in collaboration with medicinal chemists and molecular biologists at Southern Research and biochemists elsewhere, Dr. Suling's lab is developing monosaccharide and disaccharide derivatives as putative inhibitors of glycosytransferases involved in the biosynthesis of the mycolylarabinogalactan component of the cell envelope.
Bacterial cell division offers another area in which to search for novel drug targets. The protein FtsZ provides an essential role in prokaryotic cell division. It is involved in the first known step in the formation of the division septum that forms prior to cell division. FtsZ is a homolog of tubulin, present in eukaryotic cells, and, as in eukaryotic cells, is a GTPase. In vitro, the protein polymerizes into structures that are similar to microtubule protofilaments. In bacteria, FtsZ assembles into a contractile ring (Z-ring) at the site of septum formation in cell division. A collaborative effort with medicinal chemists and biochemists at Southern Research has led to the discovery of 3-deazapteridine derivatives (2-alkoxycarbonylaminopyridines) that inhibit FtsZ, but not tubulin, polymerization. Efforts are underway to optimize this chemical class into a chemotherapeutic agent through modifications of the core molecule.
Dr. Suling believes that enzymes in the folate biosynthetic pathway also offer good targets for the development of antimycobacterial drugs. This pathway produces derivatives of tetrahydrofolate that participate in a variety of biochemical functions involving single-carbon transfers at various oxidation states. These coenzymes of folate participate in the biosynthesis of thymidylate, purine nucleotides, glycine, serine and methionine. Inhibition of enzymes in the folate pathway depletes the pool of tetrahydrofolate derivatives and eventually inhibits DNA, RNA and protein synthesis.
Studies have been underway in collaboration with others at Southern Research and elsewhere to design selective inhibitors of mycobacterial dihydrofolate reductase which, with NADPH cofactor, reduces dihydrofolate to tetrahydrofolate. Although dihydrofolate reductase is found also in vertebrates, the enzyme in each taxonomic class differs to an extent that it has been possible to develop selective inhibitors. An example is the antibacterial drug trimethoprim, which is several orders of magnitude more active against the bacterial enzyme than the vertebrate enzyme. Both M. avium and M. tuberculosis are resistant to trimethoprim. This, we discovered, was due to their dihydrofolate reductase being resistant to the drug. Although the lab later developed potent inhibitors (2, 4-diamino-5-deaza-5-methyl-6-substituted pteridines) to the M. avium enzyme, it was found that M. tuberculosis dihydrofolate reductase was relatively resistant to these compounds, as was also human dihydrofolate reductase. Studies are now underway to develop selective inhibitors of the M. tuberculosis enzyme. In conjunction with these studies, X-ray crystallography is being performed at Southern Research to design new and improved inhibitors of the M. tuberculosis enzyme.
Other enzymes in the folate pathway that are under investigation as drug targets include dihydroneopterin aldolase and 6-hydroxymethyl-7, 8-dihydropterin pyrophosphokinase. These enzymes are located early in the folate pathway and neither is present in vertebrate cells which, unlike many bacteria and fungi, must obtain folates exogenously through active transport prior to their reduction by dihydrofolate reductase. This fact makes dihydroneopterin aldolase and 6-hydroxymethyl-7, 8-dihydropterin pyrophosphokinase attractive drug targets. There is also genetic evidence reported by others that the dihydroneopterin aldolase gene, folB, is an essential gene.