The prokaryotic fatty acid biosynthesis pathway constitutes a potentially rich source of essential and novel targets for selective antibacterial drug development. The overall aim of this proposal is to develop a novel class of orally bioavailable, developable preclinical lead molecules that are potent and specific inhibitors of bacterial b-ketoacyl-ACP synthases and possess antibacterial activity against multi-drug resistant Mycobacterium tuberculosis (MDRTB), Staphylococcus aureus (MRSA) and enterococci (VRE). These novel antibiotics will be obtained by the construction of focused combinatorial chemical libraries designed using the three- dimensional structure of FabB complexed with the thiotetronic acid thiolactomycin (TLM). Thiolactomycin is an excellent candidate upon which to base an optimization strategy. In vitro and in vivo antibacterial activity have already been demonstrated for TLM against the target organisms and it has been shown to have physicochemical properties compatible with being orally bioavailable and non-toxic. In order to achieve-the required therapeutic product profile, improvements in biological activity are required and we have demonstrated numerous times that these can be achieved by intensive combinatorial and array chemistry in combination with structure-based design. Thiolactomycin has never been the subject of such a medicinal chemistry program. b- ketoacyl-ACP synthases will be cloned, expressed, purified and crystallized from key pathogens, including the above, and assays configured to permit high throughput screening of TLM analogues. Potent leads will be the subject of state-of-the-art mechanistic enzymology, cocrystallography studies to drive SAR, in vitro and in vivo antibacterial testing and preliminary pharmacokinetic analysis to maximize the generation and optimization of genuine drug candidates. An added advantage accrues because such drugs would be insensitive to current major antibiotic resistance mechanisms. Bacterial type b- ketoacyl-ACP synthases are also present in malaria and other Apicomplexan parasites, as well as Trypanosomes. There is a distinct possibility that these serious pathogens may be included in the spectrum of activity of novel TLM analogues. SmithKline Beecham has a world- leading antibiotic franchise and is uniquely placed to drive the development of novel classes of antibacterial drugs.
| Kim, Pilho; Zhang, Yong-Mei; Shenoy, Gautham et al. (2006) Structure-activity relationships at the 5-position of thiolactomycin: an intact (5R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli. J Med Chem 49:159-71 |
