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Diverted Total Synthesis and Biological Investigation of the Cycloimidamicins

Award Number: F31AI203136
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/18/2027
PERIOD OF PERFORMANCE END DATE: 02/17/2028

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Diverted Total Synthesis and Biological Investigation of the Cycloimidamicins - PROJECT SUMMARY The threat of antibiotic resistance has now become clinically significant, with millions of cases of antibiotic- resistant infections occurring every year in the United States, accompanied by tens of thousands of deaths annually. At the forefront of this crisis are the ESKAPE pathogens, formidable bacteria with widespread multi- drug resistance, necessitating new antibiotics to feature a novel mechanism of action to be effective. Isolated in 2023, the cycloimidamicins (CIMs) are a novel class of macrocyclic antibiotics that inhibit bacterial translation via an unknown mechanism of action. Importantly, the CIMs have strong activity against ESKAPE pathogens such as Pseudomonas aeruginosa and Klebsiella pneumoniae and retain their activity against several engineered resistant strains. Interestingly, a methylation-induced polarity shift between the CIMs leads to a dramatic increase in potency. Hence, the central hypothesis of this proposal is that the cycloimidamicin scaffold can be developed into a new antibiotic with efficacy against resistant bacterial strains via a distinct ribosomal binding mode. To test this hypothesis, two Aims are proposed. Aim 1 is to achieve the first modular chemical synthesis of the CIMs according to the outlined retrosynthetic strategy (described herein). The synthetic route will then be leveraged to access an array of rational, hypothesis-driven CIM analogs via a diverted total synthesis approach. Aim 2 is to perform a full biological evaluation of the CIMs and elucidate their ribosomal binding site. To accomplish this, we will first perform a wide array of minimum inhibitory concentration assays against our in- house panels of wild type and clinical bacterial pathogens to establish a baseline bioactivity and resistance profile. We will then determine our best-in-class CIM analog by screening against our panel of ESKAPE pathogens for subsequent resistance-selection assays to determine the CIM binding site. Finally, the CIM binding mode will be validated through comprehensive biochemical assays, x-ray crystallography, and cryo-EM via a collaborative effort. These Aims will enable the discovery and optimization of novel antibiotics based on the cycloimidamicin natural product scaffold that are effective against already-resistant bacterial strains. Additionally, these Aims will establish the specific ribosomal binding mode of these antibiotics and therefore empower future therapeutic investigations into unique translation inhibitors. To help accomplish these Aims, a research training plan incorporating the following elements will be followed: (1) regular, focused feedback from the Sponsor, thesis committee, and colleagues, (2) academic proposal and presentation practice, (3) specialized training in new laboratory techniques by expert colleagues, (4) academic conference attendance, and (5) mentorship and teaching of undergraduates. This research training will take place at Emory University, which houses a multitude of state-of-the-art facilities and resources enabling modern experimental methods in chemistry and biology as well as expertise in these fields amongst faculty and students.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $50,114 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	1	8/18/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Diverted Total Synthesis and Biological Investigation of the Cycloimidamicins

Award Number: F31AI203136

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/18/2027

PERIOD OF PERFORMANCE END DATE: 02/17/2028

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