Tuesday, November 19, 2013

Design of Antibiotics that Target Biotin Metabolism by Dr. Courtney Aldrich

I attended a seminar on antibiotic design, specifically about antibiotics that target Biotin metabolism which is utilized by Mycobacterium tuberculosis, the organisms responsible for the disease, tuberculosis. Dr. Courtney Aldrich gave me my first insight into the field of medicinal chemistry and drug design. I’ll admit there are aspects of his lecture that I did not understand due to the fact that I have yet to take biochemistry, but I am excited to learn more. The last antibiotic discovery that was effective in treatment of tuberculosis took place around 4 decades ago. Some of the reasons for the hold up in the synthesis of new antibiotics are the fact that antibiotics are mechanism limited. There are only a couple pathways they can disrupt in order to successfully halt bacterial growth and the most commonly targeted are the translation pathway, DNA replication, or cell wall synthesis. According to Dr. Aldrich, new antibiotics will be developed through the use of the unbiased phenotypic whole-cell screening technique in which compounds with antibiotic activity are obtained and of those, the ones that are multi-target inhibitors are identified.

                Another technique employed in antibiotic construction is the biased-target-based rationale but limitation to this method are that it lacks proper genetic validation since it is an in vitro technique and may react differently in vivo. It has also been seen that there is rapid evolution of drug resistance to these single targeting drugs that mainly target the rate-limiting step of the chemical reaction.

                Dr. Aldrich’s research was specific to biotin metabolism in order to treat tuberculosis. Biotin is a cofactor that is involved in carboxylation of enzymes and fatty acid biosynthesis which is extremely important to all bacterial cells due to their cell wall structure. Biotin is extremely vital for the mycobacterial cell envelope because it is made up of 70% lipids by weight. Dr. Aldrich’s research was target-based and focused on specific enzymes in the biotin pathway with a focus on Bio enzyme A, a PLP dependent enzyme which causes the loss of a carbonyl that is replaced by an amine, the reduction of a cofactor. Almost all antibacterials were discovered using the method of isolating natural products and deriving the antibiotic from them, the natural product optimization method. A common question would be how to distinguish between which products should be pursued and the answer is simply that they are cherry-picked. Once compounds are selected they are tested on wildtype genes and mutated genes and successful targeting is tracked.  

The goal of an antibiotic (as well as most biochemical reactions) is a stabilized product. A specific drug that Dr. Aldrich worked with was Amiclenomycin, a Bio A inactivator that inhibits the synthetic mechanism for biotin. The inhibition mechanism is powered by ketolysis which produces a very reactive species.

My eyes were opened to the world of drug synthesis which would not be possible with organic chemistry. Understanding a variety of reactions and mechanisms has broader implications than simply being prepared for an exam, for those in the field of medicinal chemistry the research and development of such products are saving lives. I have much to learn before all of the terms and processes discussed in Dr. Aldrich’s lecture make complete sense to me, but this lecture definitely gave me a taste of a clinical application of how the things I’ve been learning throughout the semester serve the world in a variety of contexts.

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