Entries in therapeutics (2)


Fighting drug resistance with a Lego-like convergent synthesis strategy of macrolide antibiotics

Antibiotics have had a tremendous impact on human society. The rise of antibiotics in the early 20th century quasi eradicated tuberculosis and syphilis in the developed world and paved the way for a new age in medicine. Likewise, our current and unprecedented level of health and wealth can only be maintained and improved by having control over infectious diseases.

A key problem with the wide-spread use of antibiotics, however, is formation of resistance. By applying evolutionary pressure on a bacterial strain, it is only a question of time until the rapidly evolving unicellular organisms find a mutation that makes them survive the chemical attack. Very recently, it has been reported that multidrug resistant “superbugs” have developed due to overuse of antibiotics on farm animals.[1] In order to keep up with formation of resistance against current drugs it is therefore important to further keep developing new molecular structures.

Molecules that provide antibacterial activity often derive from naturally occurring ones. In particular in the middle of the 20th century, researchers sought novel natural antibiotics, elucidated their structure, and started programs to develop new drugs on this structural basis. One class of drugs that emerged from these efforts is macrolide antibiotics. Those molecules belong to the polyketide class of natural products, featuring a large lactone ring. Famous members are, for instance, eryhthromycin, which is used to treat respiratory infections, chlamydia and syphilis, and clarithromycin, which is used to treat lyme disease among others.

In order to produce and modify the structurally complicated macrolide antibiotics, researchers have mostly turned to semisynthesis by employing natural products derived from fermentation as starting materials for subsequent synthetic modifications. While elegant in many ways, this approach only provides a limited number of possible modifications and thus a small number of potential new drug candidates.

An international team led by Andrew Myers including Daniel Hog and Xiang Zhou has now disclosed “A platform for the discovery of new macrolide antibiotics”.[2] Using simple and modular building blocks, they synthesized over 300 macrolides in a convergent synthesis strategy. This elegant and efficient strategy allowed modifying both the core and installing further substituents in an unprecedented versatility. As a result, structures can be diversified in an “almost exponential manner”. The authors anticipate that “many thousands of novel macrolide structures can be prepared for evaluation as potential antibiotics using the present synthetic platform” and conclude that “developing similar convergent routes to other naturally occurring antibiotic families may accelerate the discovery of new therapeutic agents for human infectious diseases.”    



[1] http://www.nytimes.com/2015/10/20/business/energy-environment/taking-on-the-superbugs-antibiotics.html?_r=0

[2] http://www.nature.com/nature/journal/v533/n7603/full/nature17967.html


Exciting promise for epigenetic-based pain therapeutics

As a consequence of growing up in Buffalo, NY, I have never adjusted well to high temperatures. This became a bit of a problem in graduate school, when I lived in Baltimore, MD (summer average temperature is around 90F!). One morning I was particularly motivated and went for a jog, it was only 80 degrees; I thought I would be fine!  However, when I was only two miles into my routine (no problem at that time…) I broke out in a cold sweat, became dizzy, and felt instantly nauseous and weak. It was AWFUL! Luckily, I recognized these symptoms and rested in the shade until I could safely walk home. But what if these symptoms didn’t occur? What if I hadn’t felt awful? Likely, I would have suffered a serious heat stroke. Such what-if’s are a constant concern for people with CIP (congenital insensitivity to pain). Without pain, everyday activities become dangerous.

CIP is a rare autosomal recessive genetic disease that results in a complete loss of pain perception1. Patients cannot feel extreme injuries such as a broken bone or a third-degree burn2,3,4. Consequently, continual self-mutilation results in lesions to the tongue, bone deformities, corneal scarring, and neuropathic joints5. Patients also cannot recognize signs of internal illness such as infection4. Therefore, those with CIP must diligently survey themselves to access their health daily.

Recently, Chen et al. discovered a set of CIP-related mutations in the PRDM12 gene5. PRDM12 encodes a SET domain protein expressed in nociceptors (pain-sensing neurons) and is required for nociceptor development5. Unlike most SET domain proteins, PRDM12 does not have intrinsic histone methyltransferase activity; instead PRDM12 recruits G9a to dimethylate histone H3 at the lysine 9 position (H3K9me2)5. CIP-related mutations disrupt G9a recruitment and therefore, the histone-modifying potential of PRDM125. Accordingly, precise localization of H3K9me2 during nociceptor development may be essential for pain sensation.

Although too little pain is dangerous, chronic pain is a huge problem for over 100 million Americans6. Inhibition of PRDM12 may provide a promising target for pain therapeutics. It will be interesting to learn the in vivo effects of PRDM12 inhibition in rodent pain models. As current opioid-based pain medications are highly addictive, new pain management treatments represent a huge medical need.


1.)  Peddareddygari, Oberoi, and Grewal (2014). Congenital Insensitivity to Pain: A Case Report and Review of the Literature. Case Reports in Neurological Medicine.

2.)  Genetics Home Reference (2012). Congenital Insensitivity to Pain. Retrieved from http://ghr.nlm.nih.gov/condition/congenital-insensitivity-to-pain

3.)  ABC News (2013). Meet the Child Who Feels No Pain. Retrieved from http://abcnews.go.com/Health/meet-toddler-feels-pain/story?id=20658484&page=2

4.)  Chen et al. (2015). Transcriptional regulator PRDM12 is essential for human pain perception. Nature Genetics Letters.