David Baker’s research group uses biochemical and genetic approaches to study the cyclic nucleotide signal transduction pathways of malaria parasites. These pathways are centred on the intracellular messenger molecules cAMP and cGMP which perform a whole spectrum of cellular functions in diverse organisms. David's studies have focused on the cyclase enzymes that synthesise cyclic nucleotides, the phosphodiesterases that degrade them, but also on the protein kinases that are activated by cGMP (PKG) and cAMP (PKA). David's group have found that in Plasmodium falciparum cGMP and PKG play an essential role in triggering the activation of mature sexual parasite forms (gametocytes) which are required to transmit disease to the mosquito vector. It is now becoming clear that cGMP signalling and the PKG enzyme are vital for multiple parasite stages; for example using specific PKG inhibitors in conjunction with inhibitor-insensitive transgenic parasites, David's team in collaboration with Mike Blackman at the Francis Crick Institute, have demonstrated that asexual blood stage egress is blocked if PKG is inhibited or conditionally disrupted. This collaboration has also recently demonstrated an essential role of cAMP and PKA signalling for erythrocyte invasion by P. falciparum merozoites. Through collaboration with Mathieu Brochet at the University of Geneva, David has shown that PKG activity stimulates calcium release required for merozoite egress and that this is likely mediated through regulation of phosphoinositide metablism. Since drug resistance is a huge problem, David is also investigating whether cyclic nucleotide signalling pathways could be targeted in the development of novel antimalarial drugs. This is funded primarily by a Wellcome Trust Innovator Award in partnership with Salvensis and the Medicines for Malaria Venture (MMV).

David received a Wellcome Trust Senior Investigator Award in 2015. This was a joint award with Professor Mike Blackman at the Francis Crick Institute that focused on the cGMP signalling pathway in malaria parasites. A second joint Investigator Award to David and Mike will start in mid-2021 and will focus on the downstream players of cAMP signalling in blood stage malaria parasites.