Grant: Collaborative Health Research Projects

This project focuses on producing new antibiotic drugs that are ""broad-spectrum"" to treat all types of drug-resistant bacterial infections as well as, potentially, tuberculosis and malaria. Drug resistance is a growing problem that has made current antibiotics much less effective than before. This is of special concern in resistant strains of Staph. aureus (the ""superbug"" MRSA); Gram-negative infections caused by E. coli; so-called ""XDR"" tuberculosis caused by strains of Mycobacterium tuberculosis; and malaria, the causative agent of which is Pl. falciparum. All of these diverse diseases can be targeted by the same drug, provided the mechanism of action is present in all of them. This proposal uses novel compounds that kill MRSA, developed in previous work, as a starting point for making such broad-spectrum antibiotics. Our compounds target ACP synthase, a key enzyme that is essential for lipid synthesis and has a common structure in all of the above infectious agents, but is very different in our cells. In this work, biological tests will be designed to measure the antibiotic effectiveness of over 500 previously-made compounds for three species of bacteria causing infection, tuberculosis, and malaria, respectively. Then the compounds will be screened to determine which represent the best ""stepping stones"" to better activity. Over 75 compounds will then be made using the information from that screening programme, with a view to improving the potency of the ""hit"" compounds. The best of these new compounds will then be evaluated in established disease models of infection, tuberculosis, and/or malaria as appropriate. The goal is to produce a potent broad-spectrum antibiotic for these diseases.