Tuesday, March 15, 2016

Tarocin refurbishes β-lactam activity against MRSA


I wonder if antibiotic sensitive Staphylococcus aureus exists in clinical samples. Almost every strain I have been looking at is now MRSA. Many strains have gone beyond and have acquired a variety of properties. S aureus forms one of those glorified pathogens and forms one of the most common pathogen under Gram positive cocci category. Other species of Staphylococcus is also slowly showing up at higher rates. S aureus is part of the ESKAPE group of organisms all well known for their ability for infection and antibiotic resistance.

Of all the classes of antibiotics, β-lactam antibiotics are the most preferred members. Among the sub classes, Cephalosporin's are the favourites. They are further classified into different generations depending on their development and activity. Currently 5 generations are recognised. The 5th generation cephalosporins are considered to be the latest among the group and have broad spectrum activity. Well known examples of 5th Gen Cephalosporin's include- Ceftaroline and Ceftobiprole, both of which are well indicated against MRSA. In a post on Avibactam long ago, I mentioned that simply inventing a more complicated β-lactam antibiotic is not going to work for a long time. We need a magical way to refurbish the older antibiotics. One way of achieving it is to find new β-lactamase inhibitor.

Fig 1: Structure of Tarocin A and Tarocin B.
MRSA forms a special case of interest since a majority of the MRSA doesn't have a β-lactamase to begin with. Instead they have a horizontally acquired alternative penicillin-binding protein, Pbp2a. More recently studies have shown that MRSA can be rendered susceptible again, provided we interfere with teichoic acid biosynthesis. There are many different Wall teichoic acid inhibitors (WTAi) such as Targocil,  L275, L638, L524, L555. However, they have efficacy and toxicity issues. In an attempt to resolve the issue a team led by Roemer (Merck Research Laboratory) screened 2.8 million small molecules for effective teichoic acid inhibitors. They found 2 chemicals inhibiting the first step of teichoic acid synthesis. The chemicals where named as tarocins- A and B. See Fig 1 for chemical structure. A derivative named as tarocin A1 displayed complete depletion of the wall teichoic acid polymer.

Further analysis showed that tarocins by themselves had least bioactivity and no cytotoxicity. The target of activity was also confirmed as TarO by finding resistant mutants and subsequent whole genome sequencing. As a proof of concept, researchers also tested for its synergistic activity with several β-lactam's and the results are quite convincing.

Roemer is optimistic about the findings and comments, "It turns out that clinical trials [are] much more straightforward if the adjuvant is non-bioactive. Compared with an entirely new antibiotic that itself kills bugs, the regulatory path to clinical development of an inactive adjuvant is faster, easier and less costly. It opens up more targets and new chemical space to consider. You just have to pair it with an existing antibiotic.”
Hao Wang,Charles J. Gill, Sang H. Lee,Paul Mann,Paul Zuck, Timothy C. Meredith,Nicholas Murgolo, Xinwei She, Susan Kales, Lianzhu Liang, Jenny Liu, Jin Wu, John Santa Maria, Jing Su, Jianping Pan, Judy Hailey, Debra Mcguinness, Christopher M. Tan, Amy Fla (2013). Discovery of Novel Wall Teichoic Acid Inhibitors as Effective anti-MRSA β-lactam Combination Agents Chemical Biology, 20 (2), 272-284 : doi: 10.1016/j.chembiol.2012.11.013

Sang Ho Lee, Hao Wang, Marc Labroli, Sandra Koseoglu, Paul Zuck, Todd Mayhood, Charles Gill, Paul Mann, Xinwei Sher, Sookhee Ha, Shu-Wei Yang, Mihir Mandal, Christine Yang, Lianzhu Liang, Zheng Tan, Paul Tawa, Yan Hou, Reshma Kuvelkar, Kristine DeVito, Xi (2016). Discovery of Novel Wall Teichoic Acid Inhibitors as Effective anti-MRSA β-lactam Combination Agents Science Translational Medicine, 8 (329) : DOI: 10.1126/scitranslmed.aad7364

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