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Mechanistic and Pharmacological studies of transition-metal ABC transporters that are essential to bacterial virulence

Final Report Summary - METAL TRANSPORTERS (Mechanistic and Pharmacological studies of transition-metal ABC transporters that are essential to bacterial virulence.)

Over the past years, we have witnessed a marked increase in the emergence of bacterial antibiotic resistance. Moreover, there are very few new antibiotics in the research and development pipeline, underscoring the necessity of novel anti-bacterial solutions.
To address this issue, the EU-funded METAL TRANSPORTERS (Mechanistic and pharmacological studies of transition-metal ABC transporters that are essential to bacterial virulence) project will investigate the potential of ATP binding cassette (ABC) transporters of transition metals as novel antibiotic targets. ABC transporters are transmembrane proteins that utilise the energy of ATP to carry out vital biological processes including the transfer of various molecules across membranes.
We aim to describe the function of ABC transporters and characterise the mechanism of action of the newly identified Bacillus anthracis MntABC transporter. The ultimate goal is to demonstrate that ABC proteins are attractive therapeutic targets and to lay the foundation for developing novel effective antibacterials.
Since the beginning of the project, scientists have performed a mechanistic comparison of the function of various bacterial ABC transporters to determine their structure and mechanism of action. They were able to discover unique and previously unknown aspects of the function of ABC transporters. Specifically, the scientists showed that different ABC transporters operate by different mechanisms in correlation to their physiological role. They also observed that an ABC transporter displays a phenomenon termed “conformational memory” where the protein molecule “remembers” its conformational past. They focused on the MntABC transporter that is a major virulence determinate of Bacillus anthracis, the causative agent of ANTHRAX.
They have built a model of components of the MntABC transporter, validated the correctness of their model and showed that for the function of MntABC is to import manganese. Therefore, if we can inhibit manganese uptake by MntABC we block the development of ANTHRAX.
From a therapeutic perspective, the scientists continued their search for a small molecule that could potentially inhibit MntABC activity. After testing an initial subset of 25 promising molecules the scientist have identified the most promising one and are currently working to improve its inhibitory efficacy.
But perhaps most importantly the scientists found that zinc, a metal commonly found in over the counter commercial vitamins, may be used as a potent inhibitor of MntABC activity. This suggests that progression of ANTHRAX may be staled simply by a rich zinc diet.
The METAL TRANSPORTERS study outcomes should advance our understanding of the role of ABC transporters in bacterial virulence and identify drugs that could serve as antibiotics.