Mtb CoaBC · CoaBC from the Coenzyme A pathway of Mycobacterium tuberculosis as an antimicrobial drug target
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-04-19 → 2021-08-24
- EU contribution
- €183,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
CoaBC from the Coenzyme A pathway of Mycobacterium tuberculosis as an antimicrobial drug target
Tuberculosis (TB) is one of the top ten causes of death worldwide, accounting for 1.8 million fatalities per year. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (Mtb), the pathogen causing TB, is of particular concern. To overcome this substantial threat to public health, it will be crucial to have access to new anti-tubercular drugs. The biosynthesis pathway of coenzyme A (CoA) is essential in bacteria, and inhibiting the CoA pathway is considered a viable antibiotic strategy that has not yet been thoroughly explored. In Mtb, an important step in the biosynthesis of CoA is the formation of 4’-phosphopantetheine from 4’-phosphopantothenate and L-cysteine. This two-step process is catalysed by the bifunctional enzyme CoaBC. Given its significant different to the human orthologue, CoaBC is considered a highly promising target for the development of novel selective anti-tubercular drugs. While there is genetic evidence indicating that CoaBC is a vulnerable target in Mtb, at the start of this project, there was no existing inhibitors of CoaBC that also showed activity on whole-cell Mtb. Our aim was to develop first CoaBC inhibitors that would also be active on Mtb. This would confirm that targeting CoaBC is a promising new antitubercular strategy with potential against MDR and XDR strains, underlining the viability CoaBC as a new TB drug target.
Data: CORDIS, © European Union
Project objective
The increasing prevalence of drug-resistant microorganisms worldwide and the shortage of novel antimicrobial chemotherapeutics in the pipeline places our capacity to treat infectious diseases under serious threat. Antimicrobial chemotherapies with novel modes of action are desperately needed. However, the development of such therapies is a formidable task associated with a high failure rate. This has been partly attributed to the limited diversity of high-throughput screening libraries and difficulties converting potent inhibitors of targets into cell-active leads. We intend to use a novel, unified and efficient approach to target, in multiple pathogenic microorganisms, the conserved biosynthesis pathway of Coenzyme A (CoA), an essential enzyme cofactor. Using powerful “fragment-based” approaches, pioneered in Cambridge, we have developed a series of highly potent inhibitors of the most vulnerable enzyme target in the bacterial CoA biosynthesis pathway of Mycobacterium tuberculosis (Mtb), Mtb CoaBC, a target which has recently been validated in experiments using conditional knockdown mutants in CoA pathway genes. We will focus our initial efforts in confirming that tuberculosis (TB) can be combatted with small molecule CoaBC inhibitors. In addition, we propose to assess the cross-species activity of these inhibitors on a panel of other pathogenic microorganisms, leveraging this research and potentially generating leads for antibiotics against these other pathogens.
Original text from CORDIS.
Participants
- THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGECoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union