Monday, November 18, 2013

Dr. Aldrich on the synthesis of new TB drugs

On 11/15, the chemistry department seminar speaker was Courtney Aldrich, whose talk was on “Design of Antibiotics that Target Biotin Metabolism”. Dr. Aldrich, a PhD from the University of Minnesota in the department of medicinal chemistry.  His focus is on the synthesis of new antibiotics for tuberculosis.
Dr. Aldrich opened the seminar by discussing a brief history of antibiotic development. He discussed the first antibiotics which were mainly sulfide-containing antibiotics being developed in Germany in the early 1930’s and lamented that since 1987 scientists have created no new antibiotics, a period we now call “the discovery void.”  He explained that most antibiotics are created in one of two ways:  phenotypic whole-cell screening or biased-target based rationale. He states that his lab began new work on a biased-target based procedure to affect the rate-limiting step of biotin.  He explained that bacteria, unlike humans have to synthesize their own vitamins and minerals; cofactors.  Biotin is very important in the myobacterium for lipid cell wall synthesis.

Tuberculosis has been classified as a “modern emerging infectious disease” because though we are very familiar with the standard and older forms of the disease, we are much less familiar with the newer, drug resistant and fungal forms of the disease.  TB still is the leading fatal infectious disease, with mortality rates of 1.4 million people per year.  Another complication of the treatment of TB is that the microorganisms that cause TB can be affected by other diseases: for example the treatment of TB is greatly complicated by a co-infection of HIV/AIDS.  The initial tests for trial drugs showed that the rate limiting step was slower than for clindamycin.  Dr. Aldrich and those who also worked on the study then modified the side chain of the enzymes to catalyze the reaction of the synthesis of the lipids for the cell wall from biotin. By inhibiting the t-step, the biotin is produced in a less efficient manner and the bacteria cannot multiply.  Eventually the bacteria will die. It was then found that the biotinylated proteins were very effective against M strains of TB but not fungal strains.  The drug can now be targeted for myobacterium etiologies of TB.  The drugs are now being targeted for myobacterium specifically.  Dr. Aldrich concluded by stating that the development of these new biotin-targeted drugs can be effective as a product of  biased-target based rationale but he does note that it is very important to recognize the drug’s use in vivo in the body-for the drugs he has been working to synthesize as well as all other drugs.

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