Acinetobacter baumannii is a gram-negative pathogen that is highly resistant to multiple drug classes. Such resistance, alongside effective virulence factors, has allowed this pathogen to thrive in modern medical environments, posing a major threat to human health. Recently, the World Health Organisation listed A. baumannii as priority one for the research and development of new antibiotics. Fatty acids are essential cell membrane components and the bacterial type two fatty acid synthesis (FASII) pathway contains a number of enzymes recognised as potential targets for the development of inhibitors. This pathway is favourable due to the distinct differences from mammalian type one fatty acid synthesis (FASI). In particular the first reductase enzyme, 3-oxoacyl-ACP reductase (FabG), is an attractive target for inhibition of the FASII pathway. FabG is a member of the short-chain dehydrogenase/reductase family, a class of proteins known to display a diverse range of functions whilst maintaining conserved sequence motifs and Rossmann folding patterns.
Database results show multiple sequences annotated as FabG proteins for A. baumannii. FabG homologs have been noted in other bacteria such as Mycobacterium and may play a role in bacterial virulence or survival. This project aimed to find the structure of FabG homologs through recombinant protein expression, purification and crystallization. Diffraction data was collected at the Australian Synchrotron and used to solve the enzyme structure. The structural analysis was complemented with functional data, enabling the assessment of enzyme activity. Interestingly, results characterised both a low molecular weight FabG and high molecular weight FabG from A. baumannii. Inhibitors designed to target FabG proteins and prevent bacterial fatty acid synthesis are currently under investigation and may provide a platform for drug design against ‘superbugs’ including Acinetobacter baumannii.