CC4CARB is interested in addressing the unmet medical needs via an innovative, differentiated approach of serious and urgent Gram-negative threats as listed by the Centers for Disease Control and Prevention (CDC) in their 2019 Antibiotic Resistance Threats Report. If the proposed scaffold is effective against Gram-negative serious and urgent threats, it would be noted as a “strength” for advancement into production of an Individual Library Production Plan (ILPP). The urgent and serious Gram-positive threats and drug-resistant tuberculosis are also of interest but to a lesser extent than Gram-negative bacteria.
The scoring system for CC4CARB makes use of the 9-point rating scale (1 = exceptional; 9 = poor) used in NIH grant applications as seen below. The overall impact score is the summary outcome scoring of the 3 main proposal categories which are Significance, Innovation, and Approach/Feasibility.
The SAB reviewer scoring guide is provided here as a resource for the submitter to know exactly how the proposal will be reviewed and scored.
| Score | Impact | Descriptor | Additional Guidance |
|---|---|---|---|
| 1 | High | Exceptional | Exceptionally strong with essentially no weaknesses |
| 2 | High | Outstanding | Extremely strong with negligible weaknesses |
| 3 | High | Excellent | Very strong with only some minor weaknesses |
| 4 | Moderate | Very Good | Strong but with numerous minor weaknesses |
| 5 | Moderate | Good | Strong but with at least one moderate weakness |
| 6 | Moderate | Satisfactory | Some strengths but also some moderate weaknesses |
| 7 | Low | Fair | Some strengths but with at least one major weakness |
| 8 | Low | Marginal | A few strengths and a few major weaknesses |
| 9 | Low | Poor | Very few strengths and numerous major weaknesses |
If your application is approved, a contact person at CC4CARB will be assigned to your application and a kick-off meeting will be scheduled at a mutually convenient time. The kick-off meeting will be an opportunity to present the project to the CC4CARB team and orient the team on the preparation of the Individual Library Production Plan (ILPP) document.
CC4CARB is a global outreach program for the scientific community to facilitate the synthesis and delivery of antimicrobial matter. Any researcher can submit a scaffold proposal for consideration, and any researcher can request compounds from the Collection. The Scientific Advisory Board (SAB) reviews and approves scaffold proposals and the NIAID reviews/approves compound requests and Individual Library Production Plans (ILPPs).
CC4CARB welcomes the prudent support for your client. If your client is fine with you submitting a scaffold idea to progress their research, feel free to submit the scaffold proposal for consideration.
At present, NIAID is interested in Gram-negative hits or leads, but the team will use Gram-negative penetration models to potentially broaden the activity for a narrow Gram-positive agent. NIAID may also perform minimum inhibitory concentration (MIC) screening on select drug-resistant strains of Gram-negatives (E. coli, K. pnuemoniae, A baumannii, P. aeruginosa, N. gonorrhoeae) and a Gram-positive (S. aureus).
If an antifungal hit has known activity against Gram-negatives, the submitter can tout the prokaryotic activity over the antifungal activity. If the scaffold proposal and Individual Library Production Plan (ILPP) are approved, the submitter can utilize the compound for antifungal screening but should also test the compound for Gram-negative activity. CC4CARB may also submit the compound for MIC testing on the listed prokaryotes.
If you know of activity (MIC) on your scaffold idea, include this information in the scaffold proposal. Also, if you have any in vivo or in vitro results supportive of analogs of the scaffold, please add the information in the scaffold proposal.
If you have known hits on a novel scaffold, that alone is enough to showcase its potential for the program. If more in vitro characteristics are known, that should be noted in the proposal. Knowing a minimum inhibitory concentration (MIC) is convincing, however, also relaying whether the scaffold is not cytotoxic, genotoxic, etc. is a plus but not required.
It depends on how large the peptides are and if you have a starting material or intermediate (base peptide/natural product) available that would allow us to make modifications. We have worked on projects where we modify existing peptides to change/improve their properties, increasing their Gram-negative activity. A 13-28mer may be within the scope of CC4CARB depending on the structure. In your scaffold proposal, it is suggested to include the structure of your unique scaffold, and if possible, also proposed post-peptide synthesis modifications to alter the properties.
Any compounds approved for research that result in a publication or presentation must acknowledge the CC4CARB NIH initiative. The acknowledgement should read:
This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Disease, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N93021C00002.
Upon request from the submitter, RTI may delay public disclosure of the chemical structures and associated data of compounds synthesized by CC4CARB for up to 18 months. This “embargo” period shall apply equally and simultaneously to all compounds in the ILPP to which the embargo applies. The embargo period shall commence from the earliest date of COR approval of the ILPP to which the embargo applies. Structures added to an embargoed ILPP by amendment shall be subject to the embargo as if they had been present in the ILPP at the earliest approval date of the ILPP. An embargo period may be extended beyond 18 months by written approval of the COR. Intellectual Property (IP) inventorship is subject to the rules established by the organization issuing the IP.
Yes, if an idea or scaffold is already under a patent, we can work within the patent to produce analogs.
A proposal will first undergo an administrative and basic technical review for relevance to the program. Once officially accepted into the review process, the SAB will review the proposal electronically, and will then discuss the proposal at the next SAB meeting, similar to a typical NIH review. A decision to accept or reject a proposal will then be made by RTI, and the submitter will be notified. The SAB reviewer comments will be included in the notification. This process can take up to 2 months, depending on issues with submission and timing with the SAB schedule.
Once a proposal is accepted into the program, RTI and the submitter will undergo a design process to produce an ILPP. This typically takes 4-6 weeks. RTI and the submitter will first meet to discuss the project. The submitter will provide RTI with the information about synthesized analogs and corresponding data (if any). RTI will then design novel analogs, with or without the help of the submitter. An ILPP will be produced and submitted to NIAID for approval once the submitter agrees. ILPPs can be amended at any time, typically by augmentation.
The turnaround for compounds depends on the complexity of the synthesis and the availability of a chemist. Typically, 1 chemist is allocated for an Individual Library Production Plan (ILPP) and CC4CARB has a capacity of up to 15 medicinal chemists. If space is available, an approved ILPP can progress to the synthesis queue rather quickly and would likely take between 9-12 months to complete. Once the resources are completely allocated, ILPPs will enter into a prioritized list with the highest scoring Gram-negative proposals being prioritized, followed by the highest scoring Gram-positive proposals.
If approved, RTI will work in conjunction with the proposal submitter (if preferred) to draft an Individual Library Production Plan (ILPP) for NIAID’s approval. RTI involvement will depend entirely on the submitter. RTI can design all the compounds, or none of them if the submitter wants to design all of the compounds. For each approved scaffold, the submitter will be compensated up to $1500/ILPP.
Requests for additional compound beyond the at least 25 mg synthesized by CC4CARB should be directed to the NIAID. Scaleup could be done by CC4CARB, if approved by NIAID, or could be done via other pre-clinical resources at NIAID.
CC4CARB will provide the submitter with 5 mg of each compound, as a solid or oil. The remaining material (at least 20 mg) will in part be used to make 6.4 mg/L and 10 mM solutions in DMSO for use in libraries.
Any antimicrobial researcher worldwide can request compounds from the CC4CARB Collection. Researchers studying Gram-positive bacteria, mycobacteria, and antifungals can request compounds. However, should the material be low in amounts, those compounds would be reserved for Gram-negative research. All compound requests are approved by the NIAID COR.
Compound shipments will be processed at the expense of CC4CARB. However, the recipient is responsible for importation into their given country if outside of the US.
We can save you time. All compounds will arrive already plated and ready for your use — no need for weighing or plating in your lab.
We can serve as a direct means of distributing any of your unused novel compounds to interested antimicrobial researchers. When we receive your compounds, we will plate them, so they are in a format that is readily available for distribution and use by researchers. CC4CARB aims to facilitate collaborations among researchers.
Select compounds may be screened for MICs against select drug-resistant and wild type strains of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, and Neisseria gonorrhoeae. When performed, MIC testing results will be provided to the donator. If a hit is noted, a scaffold proposal can be submitted to CC4CARB for consideration in making analogs of the hit.
Shipping is free of charge to the requestor. A CC4CARB representative will provide you with a prepaid shipping label, draft proforma invoice, and draft packaging list to facilitate transfer of the compounds to RTI International. RTI Logistics will facilitate importation of shipments from outside the United States.