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Abyssomicin C Truncated derivatives against Antimicrobial Resistance

Periodic Reporting for period 1 - ACT against AMR (Abyssomicin C Truncated derivatives against Antimicrobial Resistance)

Reporting period: 2015-05-01 to 2017-04-30

Many recent human activities have strongly influenced our global environment, often in ways we have not been able to predict. An example is our use of antibiotics.

The discovery of antimicrobials and their intense use, which started in the 1940s, had a deep impact on the human welfare, which over the last six decades has drastically improved. Their discovery has increased life expectancy considerably and has allowed the global health to reach higher standards. However, especially in the past decade, we have witnessed the exponential growth of antimicrobial resistant (AMR) bacteria, a threat that casts shadows over the medical “miracles” we take for granted. AMR bacteria, also known as “SuperBugs”, are normal pathogenic bacteria that have developed a resistance against commonly use antibiotics. This makes them resistant to treatments and potentially lethal.
This project aims to offer a solid solution to the dwindling effectiveness of antibiotics against infectious diseases caused by the development of AMR bacteria.

To achieve this goal we took as model abyssomicin C, which is a natural product isolated from an actinobacter found in deep-sea sediment of the Sea of Japan. Studies performed on this compound showed that it possess interesting antimicrobial activities in particular against AMR bacteria.

The core of this proposal is to implement an innovative synthetic strategy to access truncated derivatives of abyssomicin C. The creation of a number of structurally related compounds together with computational studies will allow the identification of new potent antimicrobial agents, an important countermeasure against AMR bacteria.

If successful, this project could have a deep impact not only in the scientific community but also on the healthcare systems in Europe and globally.
During the all length of this project we targeted the synthesis of truncated derivatives of Abyssomicin C (a natural product that exhibited impressive antimicrobial proprieties against AMR bacteria and represent the focus of the entire project). We have implemented different synthetic routes for the formation of a first library of compounds structurally related to this natural product. We then submitted these compounds to biological assays against different bacteria to test their potency as antimicrobial agents. The results obtained by these tests gave us useful information about the chemical features needed in providing a good antimicrobial profile. Capitalizing on this useful information the synthesis of a second library of compounds is currently in progress and it will soon be tested in similar biological assays.
Reiteration of synthesis of new libraries and their biological evaluation will be the way to identify a compound which will be a potent antibiotic and will be characterized by minor or irrelevant side effects.
Especially during the first leg of this project we have been focusing on the assembly of robust synthetic routes for the synthesis of abyssomicin C truncated derivatives and a number of different advanced synthetic intermediates. These routes allowed us to rapidly access molecules that can easily be converted in potential antibiotics that will be tested against different strains of bacteria.
The identification of a potent new drug candidate is paramount for the creation of an effective defense against AMR bacteria. Due to the peculiar mode of action of abyssomicin C, that differ from the majority of the commonly used antibiotics, we aim to facilitate the identification of a drug that will have little or no chance to meet bacteria with preexisting resistance. This means that the potential drug will represent a fundamental lifesaving tool to fight infectious diseases created by AMR bacteria.
Abyssomicin C