Drug Discovery from Slow Growing and Rare Microbial Species

DESCRIPTION provided by applicant The overall goal of this project is to discover novel antibiotics to combat important drug resistant pathogens We are running out of treatment options for pathogens such as S aureus MRSA vancomycin resistant Enterococci VRE multidrug resistant P aeruginosa A baumannii ESBL and New Delhi metallo b lactamase producing Enterobacteriaceae and M tuberculosis Only novel antibiotics have been introduced in the past thirty years linezolid daptomycin and fidaxomicin Linezolid and fidaxomicin were discovered in the s but did not appear sufficiently attractive at the time With this pace of discovery it is not surprising that resistance is on the rise It is becoming increasingly apparent that the bottleneck in antibiotic discovery is the lack of good starting compounds Not a single drug came out of HTS of synthetic compound libraries Secondary metabolites produced by actinomycetes have been the main source of antibiotics but this resource was over mined At the same time there is a potentially very large untapped source of natural products previously uncultured bacteria that make up the vast majority of all bacterial species Slow growing species that require months to form colonies on a Petri dish are an important component of this majority We reasoned that slow growers may actually represent dormant forms of bacteria and will rapidly grow upon reinoculation The majority of slow growers can indeed be rapidly cultured upon reinoculation and many of the isolates represent previously unknown species and genera In Phase I we developed a method to simultaneously isolate and culture slow growers by placing individual cells in wells of a microtiter plate Screening of these isolates produced new antimicrobial compounds including Novo that acts specifically against M tuberculosis The target of Novo is the ClpC subunit of the essential mycobacterial ClpP protease Novo has low cytotoxicity favorable tolerability and blood levels in mice We will examine efficacy of Novo in mouse models of tuberculosis Further development of our three novel antibacterials are a major focus of Phase II However we recognize that only a small fraction of leads makes it to a drug Thus we will also undertake a large scale discovery effort to identify additional antibacterials which will enter validation as they become available Novel compounds will be examined for spectrum potency resistance development stability mechanism of action and novelty of structure Leads that emerge will be tested in mouse models of infection The end result of Phase II will be three lead compounds showing efficacy in animal models This will enable subsequent preclinical development towards an IND clinical studies and FDA approval of a new therapeutic We believe this strategy advancing leads while backing them with a discovery pipeline greatly increases the chances for the projectandapos s success PUBLIC HEALTH RELEVANCE The overall goal of the project is to use our innovative technologies to discover new antibacterial compounds Multi drug resistant bacterial pathogens are on the rise and have become a major public health problem The continuing addition of new antibacterial compounds without cross resistance to current antibiotics is the only way to effectively manage the crisis