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Development of novel metallo-beta-lactamase inhibitors for the treatment of multi-drug resistant bacteria.


   Doctoral College

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  Dr L Bowler, Dr Graham Pattison, Dr Gerry Gallacher  No more applications being accepted  Competition Funded PhD Project (UK Students Only)

About the Project

Since the introduction of the first beta-lactam antibiotic, penicillin, there has been a growing problem with bacterial resistance to this class of drugs. This is now presenting as a significant threat to the health of society globally. As this situation worsens, it is likely that we may soon find ourselves in a situation where common infectious diseases, currently easily treatable with antimicrobials, become untreatable and once again life-threatening. This can be countered by development of new classes of antibiotics or the introduction of inhibitors to inactivate the bacterial enzymes that often mediate resistance.

The carbapenem beta-lactams were, until recently, among the last remaining antibiotics available for use against otherwise completely resistant bacteria. However, in 2009 a strain of Klebsiella pneumonia was isolated that was resistant to all known beta-lactam antibiotics, including the carbapenems. This strain expressed a novel enzyme: NDM-1 (New Delhi Metallo-beta-lactamase) which have zinc ions at their active centres. NDM-1 has since spread to other, different, bacterial species. This presents a very serious threat to public health and new inhibitors are urgently needed. Without urgent and effective action, we are heading for a post-antibiotic era, in which common infections and minor injuries can once again kill.

Most bacterial resistance to beta-lactams occurs via enzymatic hydrolysis of the amide bond of the antibiotic (the beta-lactam bond), mediated by a beta-lactamase. One strategy for restoring drug-activity is to design and synthesise putative inhibitors of these ‘resistance enzymes’. If effective, the antibiotic could then be co-administered with the inhibitor, eliminating the effect of the bacterial enzyme and restoring the efficacy of the antibiotic drug.

The student will use state-of-the-art microbiological, computational modelling and medicinal chemistry techniques to investigate and design molecular inhibitors that will bind strongly to the active site of NDM-1 beta-lactamase. These will be based on scaffolds such as sulfonamides or boronic acids that should have a similar shape to mimic the transition state of hydrolysis of the beta-lactam antibiotic. The inhibitors will be designed so that they sit in and block the active site of the beta-lactamase, meaning that the antibiotic will not be affected by the ‘resistance enzyme’, and can still kill the bacteria effectively.

GG and LB have recent preliminary data showing that certain sulphonamide-based synthetic analogues are able to at least partially inhibit the Verona integron-encoded metallo-beta-lactamase (VIM-1) from Klebsiella pneumoniae, a metallo-beta-lactamase enzyme related to NDM-1. When co-administered with the carbapenem beta-lactam antibiotic Meropenem, these 'sulphonamide analogues' have reduced the minimum inhibitory concentration of Meropenem against VIM-1 producing bacteria, underlining the promise of this type of approach.

Once our existing compounds have been tested and characterized then more effective metallo-beta-lactamase inhibitors will be designed and synthesised using a broad range of modern synthetic chemistry techniques. The student will then characterise their activity and demonstrate their effectiveness against clinical isolates of beta-lactamase producing carbapenem-resistant bacterial species of clinical significance. These results will then drive the design and synthesis of more active compounds until highly active and clinically useful inhibitors are identified.

The student will learn a broad range of interdisciplinary techniques, including drug design, computational modelling, synthetic chemistry and a variety of microbiological methods, developing a well-rounded researcher ready to tackle the significant health challenges of the 21st-century.


Funding Notes

The studentship is for 3 years and consists of a full stipend, tuition fees and a travel bursary for participation by the students and supervisors in cohort building and training events related to the DTA Future Societies network programme.
Anticipated start date is 01 October 2021.
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