Provided here are samples of a completed CC4CARB proposal and an Individual Library Production Plan (ILPP). These documents are meant to provide guidance on the level of detail and context that should be reflected in a scaffold proposal. If the scaffold proposal is approved, key CC4CARB team members from RTI, the SAB, and NIH will work with the scaffold proposal’s submitter to create an ILPP.
CC4CARB Proposal Sample CC4CARB Library Design Sample (ILPP)
Center for Disease Control and Prevention
World Health Organization
The National Strategy is a plan for the U.S. to work with domestic and international partners to reduce the national and international threat of antibiotic resistance.
The National Action Plan directs federal agencies to accelerate response to antibiotic resistance by presenting coordinated, strategic actions to improve the health and well-being of all Americans across the One Health spectrum. It has pushed transformative improvements across the country that strengthen and expand the ability to respond to these threats.
A sustained and robust pipeline of new antibacterial drugs and therapies is critical to preserve public health. In recent decades, the discovery and development of new antibiotics have slowed dramatically as scientific barriers to drug discovery, regulatory challenges, and diminishing returns on investment have led major drug companies to scale back or abandon their antibiotic research. Consequently, antibiotic discovery—which peaked in the 1950s—has dropped precipitously. Of greater concern is the fact that nearly all antibiotics brought to market over the past 30 years have been variations on existing drugs.1 Every currently available antibiotic is a derivative of a class discovered between the early 1900s and 1984.
U.S. senators reintroduced the Pioneering Antimicrobial Subscriptions to End Upsurging Resistance (PASTEUR) Act to encourage innovative drug development targeting the most threatening infections, improve the appropriate use of antibiotics, and ensure domestic availability when needed.
CC4CARB is an innovative chemistry center focused on the synthesis and delivery of rationally designed focused libraries for the scientific community to use in Gram-negative antibacterial drug discovery programs. The ultimate objective of CC4CARB is to create a large collection of chemical matter specifically targeting Gram-negative antimicrobial drug discovery.
CARB-X is a global non-profit partnership dedicated to accelerating antibacterial research to tackle the global rising threat of drug-resistant bacteria. With up to US$480 million to invest in 2016-22, CARB-X funds the best science from around the world. The CARB-X portfolio is the world’s largest early development pipeline of new antibiotics, vaccines, rapid diagnostics and other products to prevent, diagnose and treat life-threatening bacterial infections.
Abstract highlights: Most small molecules are unable to rapidly traverse the outer membrane of Gram-negative bacteria and accumulate inside these cells, making the discovery of much-needed drugs against these pathogens challenging. Here we assess the ability of over 180 diverse compounds to accumulate in Escherichia coli. Computational analysis of the results reveals major differences from the retrospective studies, namely that the small molecules that are most likely to accumulate contain an amine, are amphiphilic and rigid, and have low globularity. We anticipate that these findings will aid in the discovery and development of antibiotics against Gram-negative bacteria.
Abstract highlights: The discovery of novel antibiotics is essential to combat the rise of antimicrobial resistance. While a number of initiatives are focused on advancing promising leads into the clinic, there is a dearth of effort at stimulating the early stage discovery. We present one pathway that has successfully demonstrated an ability to revitalize fundamental research and reengage researchers.
Abstract highlights: The estimate is that by 2050, there will be no effective antibiotic available, if no new drug is developed or discovered. This raises the need to search for alternative methods of controlling antibiotic-resistant pathogens. Considering this problem, the objective of this review is to outline the most frequent antibiotic-resistant bacteria and describe the advantageous and limitations of alternative methods that have been proposed to control them.
Abstract highlights: Resistance against nearly all antibiotics used clinically have been documented in bacteria. There is an ever-increasing danger caused by multidrug-resistant Gram-negative bacteria in both hospital and community settings. In Gram-negative bacteria, intrinsic resistance to currently available antibiotics is mainly due to overexpressed efflux pumps which are constitutively present and also presence of protective outer membrane.
Abstract highlights: Superbugs’ resistivity against available natural products has become an alarming global threat, causing a rapid deterioration in public health and claiming tens of thousands of lives yearly. Although the rapid discovery of small molecules from plant and microbial origin with enhanced bioactivity has provided us with some hope, a rapid hike in the resistivity of superbugs has proven to be the biggest therapeutic hurdle of all times. Moreover, several distinct mechanisms endowed by these notorious superbugs make them immune to these antibiotics subsequently causing our antibiotic wardrobe to be obsolete.
Abstract highlights: Antibiotic resistance in bacterial pathogens has currently reached very high and alarming levels. Indeed, according to a number of international bodies, this “antibiotic resistance crisis” could possibly bring us back to a “pre-antibiotic era” in the near future, if no effective actions are promptly undertaken. Unfortunately, the slow progress in antibiotic discovery and development observed during the last decades has led to a limited availability of new compounds for clinical use, thus exacerbating the burden of antibiotic resistance on morbidity and mortality rates.
Abstract highlights: An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance.Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics.