Targeting the Urgent Need for New Antibiotics against Gram-negative ‘Superbugs’

背景：世界正面临着巨大且日益增长的威胁

Background: The world is facing an enormous and growing threat from the emergence of bacterial ‘superbugs’. If bacteria continue developing resistance to multiple antibiotics at the present rate and at the same time the antibiotic pipeline continues to dry up, there could be catastrophic costs to healthcare and society globally. Numerous hospitals worldwide have experienced outbreaks of infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. All of these pathogens are on the IDSA ‘hit list’ of the six top-priority dangerous bacteria that require urgent attention to discover new antibiotics. Polymyxins (i.e. colistin and polymyxin B) are used as the ‘last-line’ of therapy for infections caused by these very problematic Gram-negative pathogens. Unfortunately, the clinical utility of polymyxins is hindered by their nephrotoxicity and poor efficacy against lung infections due to pharmacokinetic limitations. Unfortunately, plasmid-borne resistance to polymyxins has been reported recently. In essence, polymyxin resistance implies a total lack of antibiotics for treatment of deadly infections caused by these Gram-negative bacteria. Clearly, the development of new antibiotics is urgently needed. All three of these Gram-negative bacteria are the focus of this project. Research Design: Building upon our systematic polymyxin pharmacology research over the last 17 years, this project will employ our novel structure-activity relationship (SAR) and structure-toxicity relationship (STR) models to rationally develop novel, safer polymyxin-like lipopeptides that target Gram-negative ‘superbugs’ including polymyxin-resistant isolates. The Specific Aims are: (1) To employ our well established lipopeptide medicinal chemistry platform to design, synthesize and microbiologically evaluate approximately 300 novel lipopeptides against MDR K. pneumoniae, P. aeruginosa and A. baumannii; (2) To conduct lead candidate selection based upon acute toxicity, efficacy and nephrotoxicity in animal models, and MICs against an extended panel of clinical isolates. Upon completion of Aim 2, a lead candidate lipopeptide and a back-up will be selected for further development (Specific Aim 4). (3) To elucidate the mechanisms of antibacterial activity and nephrotoxicity of our polymyxin- like lipopeptides using systems pharmacology and chemical biology. These mechanistic studies will improve our SAR/STR models and benefit the IND application; and (4) To develop the lead candidate (and a back-up) for IND-enabling studies based upon evaluations of the stability, toxicity, PK and PK/PD using rodent and non- rodent models. The results from Specific Aim 4 will also provide essential efficacy and toxicity data to support future IND-enabling studies. Even though it is beyond the scope of this RFA, we are very enthusiastic that the identified lead candidate will be taken into IND-enabling studies with financial support from Rempex-MedCo. Significance: Our innovative proposal will develop much-needed safer and more efficacious polymyxins to counteract the current global health crisis caused by Gram-negative ‘superbugs’.