Acinetobacter are strictly aerobic, non-fermentative Gram-negative bacilli that are of major concern in human health, in particular the species Acinetobacter baumannii. They are responsible for clinically important infections that cause a wide variety of maladies including pneumonia, skin and wound infections, bacteremia and meningitis. In addition, A. baumannii biofilms have been implicated in cystic fibrosis, periodontitis and urinary tract infections, due to the bacteria's ability to colonize indwelling medical devices. The rise in antibiotic resistant A. baumannii has severely limited the therapeutic options for treatment, and it is widely recognized that new therapies are desperately needed which is the major goal of this STTR. Our laboratories at the University of Pennsylvania and RMH Sciences specialize in targeting the oxidative phosphorylation (OxPhos) system in new antibacterial drug discovery. The OxPhos system is the main pathway used by bacteria to produce energy in the form of ATP and is an essential process for bacterial survival. There are marked differences between the components of the bacterial OxPhos with those of mitochondria and low sequence homology between the two, suggesting that pathogen-specific therapy by this approach is possible. A high throughput screening campaign was conducted to identify A. baumannii OxPhos inhibitors. We have discovered multiple drug-like scaffolds from the HTS that selectively kill A. baumannii, with minimal inhibitory concentration (MIC) values as low as 8 mg/mL. We have identified the target of these compounds to be type 1 NADH dehydrogenase (NDH-1). In this grant, we at the Fox Chase Chemical Diversity Center, Inc. propose in Aim 1 to perform iterative medicinal chemistry to identify compounds with potent and selective antibacterial activity. Medicinal chemistry design is based upon analysis of the top hits from the HTS on which thorough literature review has been conducted, using calculated biophysical properties standard in the industry such as topological polar surface area and Log P as well as considerations of our ability to create new intellectual property.
Aim 2 involves iterative in vitr biological testing assays to track biochemical and cellular activity including systematic assays to determine the exact molecular basis for the mechanism of action. Importantly, we will confirm the lack of effect in the OxPhos associated with mammalian mitochondria, as already demonstrated for our current hits.
In Aim 3, we will utilize standard target validation and hit to lead in vitro and in vivo ADME properties including pharmacokinetic evaluation in mice, and obtain >3 advanced leads from diverse chemotypes with acceptable ADME and PK properties. Our goal is to produce potent, selective and drug-like advanced leads with MIC values of <0.4 mg/mL (<0.1 mg/mL preferred). At the completion of this proposal, we will be well suited to transition to Phase II of the STTR program, involving the pre-clinical and clinical development activities required to eventually validate the approach in patients, pursuant to eventual partnering with a major pharmaceutical company and commercialization.
The aim of this proposal is to advance a new class of antibacterial agents to treat Acinetobacter baumannii infections. Over the last 30 years resistance to the drugs used to treat these infections has risen dramatically. New drugs are therefore of urgent need.