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Discovery through chemical synthesis of antibiotics effective against modern bacterial pathogens

Award Number: R01AI168228
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT In recent decades, the emergence of antibiotic resistance in bacteria has greatly outpaced the discovery of novel antibacterial agents. This research is focused on the synthesis and biological study of antibiotics effective against these modern pathogens of urgent threat. To this end, the lincosamides have been identified as an underexploited class of antibiotics. No new lincosamide has entered the market since clindamycin was approved more than 50 years ago (FDA, 1970). Growing resistance to clindamycin and its propensity to induce life- threatening Clostridioides difficile (C. difficile) colitis have limited its utility in today’s armamentarium. Due to the structural complexity of this class of natural products, semi-synthetic strategies are insufficient to support future antibiotic drug discovery within this or related scaffolds. Here, efficient synthetic pathways will be developed and implemented to prepare a large collection of lincosamide analogs inaccessible by any other means. These include analogs of a lead candidate, iboxamycin, which features a novel bicyclic oxepanoprolinamide scaffold and is efficacious in vitro and in vivo against a broad range of multi-drug resistant (MDR) bacteria. The latter include MDR ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.), identified by the WHO as targets of highest priority in antibiotic development. By elucidating the mechanistic underpinnings and drivers of in vivo efficacy of iboxamycin and future lead antibiotics, this research will deliver multiple novel antibiotic scaffolds for preclinical exploration to target these challenging pathogens.


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: 2024 ( Subtotal = $659,558 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	3	1/24/2024	NON-COMPETING CONTINUATION	$659,558
														Subtotal = $659,558

Issue Date FY: 2023 ( Subtotal = $752,182 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	2	12/28/2022	NON-COMPETING CONTINUATION	$752,182
														Subtotal = $752,182

Issue Date FY: 2022 ( Subtotal = $766,682 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	2/10/2022	NEW	$766,682
														Subtotal = $766,682

Grand Total All Awards = $2,178,422

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Discovery through chemical synthesis of antibiotics effective against modern bacterial pathogens

Award Number: R01AI168228

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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