Celebration Waksman

Keynote address by H. Boyd Woodruff
Teaching, Research, Museum: Personal Reminiscences from the Lifetime of an ACS National Historic Landmark Laboratory

Oral history by the “Antibiotics Elders” from their tables ( roving microphone )

Natural Product Antibiotics from Actinomycetes – Past, Present and (hopefully) Future
William T. Strohl
Sr. Director, Vaccine & Biologics Research
Merck & Co., Inc., West Point, PA

The historical role of actinomycetes in natural product antibiotic discovery will be discussed, and placed in context with the current reality and projected natural product antibody discovery efforts of the future.

Why aren't we finding antibiotics as easily as we used to?
Julian Davies, FRS
Department of Microbiology and Immunology
University of British Columbia

Most of the antibiotics used today were discovered between 1940-1970; the search for new anti-infectives since that time has had limited success in finding new chemical entities with the required activity. Many reasons for this failure have been suggested, among them, that most types of antibiotic have already been found or that the number of targets in the microbial cell is limited. It is known that 99% of the bacterial kingdom with the potential to make millions of novel, bioactive small molecules is inaccessible to laboratory research. How can we access these treasures to produce new therapeutics?

Rutgers Antibiotics – Soil as a source of genes encoding the production of novel anti-microbials
Gerben Zylstra
Director, Biotechnology Center for Agriculture and the Environment
Cook College, Rutgers University

Many bacteria, particularly actinomycetes, are known to produce secondary metabolites synthesized by polyketide synthases (PKS). Bacterial polyketides are a particularly rich source of bioactive molecules many of which are of potential pharmaceutical relevance. In order to directly access PKS gene diversity in soil, we developed degenerate PCR primers for actinomycete type II ketosynthase genes. Various New Jersey soil samples were examined for their total bacterial diversity, actinomycete species diversity, and PKS gene diversity by terminal restriction fragment length polymorphism (TRFLP) of PCR products generated from DNA extracted directly from the soil samples. Based on the TRFLP patterns, two samples contained a particularly rich and unique actinomycete community and had a correspondingly high PKS gene diversity. PCR products from these and three additional samples with interesting TRFLP patterns were cloned and seven novel clades of PKS genes identified. The nucleotide sequences were between 74 and 81% identical to known sequences in GenBank, indicating a wealth of new PKS genes waiting to be discovered in nature.

Rutgers Antibiotics – Small-molecule inhibitors of bacterial RNA polymerase
Richard H. Ebright
Professor of Chemistry
Laboratory Director, Waksman Institute; Investigator
Howard Hughes Medical Institute, Rutgers University

Bacterial transcription is a validated target for antibacterial therapy. Rifampicin, rifapentine, and other ansamycin antibiotics function by binding to, and inhibiting, bacterial RNA polymerase. The ansamycin antibiotics are of major clinical importance in the treatment of bacterial infection, particularly in the treatment of tuberculosis. Due to the public-health threat posed by multi-antibiotic-resistant bacterial infection, there is an urgent need for novel classes of antibacterial agents that target bacterial RNA polymerase (and thus have the same biochemical effects as ansamycin antibiotics) but that target different, non-overlapping structural elements within bacterial RNA polymerase (and thus do not exhibit cross-resistance with ansamycin antibiotics).

We are using integrated crystallographic, biophysical, biochemical, genetic, and combinatorial-chemistry approaches to identify and characterize novel small-molecule inhibitors of bacterial RNA polymerase.

TB: Global Timebomb
Lee B. Reichman,
Professor of Medicine and Preventive Medicine and Community Health
University of Medicine and Dentistry
New Jersey-New Jersey Medical School
National Tuberculosis Laboratory, Newark

Globally, TB infects 2 billion people – one third of the world's population, newly afflicts 8.6 million annually with active TB and kills 2 million, according toWHO who has termed it “A Global Health Emergency”.The reasons for the continued epidemic include: Deterioration of infrastructure, HIV infection, foreign born individuals, neglect and inattention. Any recent decline is almost certainly due to the major infusion of support and most importantly, the directly observed therapy short course (DOTS). All cases of TB disease are curable and the disease usually becomes non-infectious within a few days from the start of treatment, but only if patients.take their medication properly. In developing nations there are , limited to almost non-existent resources, failure to adhere to international standards, availability of less efficacious, less expensive TB drugs and lack of attention to good TB practices in the private sector. With the recognition of the danger of Multidrug Resistant Tuberculosis (MDRTB), an increased level of awareness, has been engendered in the health care worker community. Balanced, rational approaches have been few and far between, but MDRTB is prevented by appropriate DOTS! The WHO/IUATLD DOTS five strategy elements receive focus.New strategies in developing new TB drugs, diagnostics, and efforts to find a new TB vaccine are wonderful advances but the global epidemic will only turn around when all basic tenants of TB control are met. Focus must be the control measures. Finally, the most important aspect of control of TB is political will to ensure proper attention, care and resources globally.

Actinomycete Secondary Metabolites: Gifts from the Soil
Arnold Demain
Research Fellow in Microbial Biochemistry
Research Institute for Scientists Emeriti (R.I.S.E.).
Drew University, Madison, NJ

Microbial secondary metabolites are extremely important to our health and to the environment in which we live. As a group that includes antibiotics, immunosuppressants, hypocholesterolemic agents, antitumor compounds, antiparasitic agents, bioherbicides and many other types of compound, they have tremendous economic importance. Antibiotics are the best known secondary metabolites. Of all the antibiotics known, 66% are produced by the actinomycetes, 55% from the genus Streptomyces alone. This amazing contribution by the soil inhabiting filamentous bacteria began in the laboratory of Selman Waksman with his students Boyd Woodruff, Hubert Lechevalier, Albert Schatz and others. Here at Rutgers university, the antibiotics streptomycin, neomycin and actinomycin D were discovered. The work that started here in the 1940's led to an amazing group of medically and agriculturally useful natural compounds produced by actinomycetes. Of special mention are antibiotics such as streptomycin, gentamicin, kanamycin, cephamycins, tetracyclines, tylosin, thienamycin, rifamycins, and the new antibiotic, daptomycin, an anti-resistance enzyme inhibitor, e.g., clavulanic acid, immunosuppressants such as sirolimus and tacrolimus, antiparasitics such as avermectin, antitumor agents such as doxorubicin and bleomycin, anticoccidial agents and animal growth promotants such as monensin and salinomycin, and insecticides such as spinosyn. The world owes much to these gifts from the soil and the gift-giving all started here in a small laboratory at Cook College, Rutgers University