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De Novo Synthesis, and Functional and Structural Characterization of Novel Aminoglycoside Analogues to Bypass Resistance Mechanisms and Optimize Selectivity

Award Number: R01AI154860
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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There is an emerging threat from multidrug-resistant Gram-negative bacterial pathogens, specifically, carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa (e.g., ESKAPE pathogens). The resulting infections are often untreatable or treatable only with toxic antimicrobials. More troubling is the fact that the incidences of these infections are occurring with increasing frequency. Therefore, the CDC now categorizes such organisms in their top antibiotic resistance threat level. New anti-infective strategies are urgently needed. This multi-PI R01 application proposes a de novo medicinal chemistry design and de novo carbohydrate synthesis approach, which when coupled with functional characterization and cryo-EM enabled structure-guided design should lead to the rapid discovery of novel aminoglycoside (AG) antimicrobials with activity against resistant Gram-negative pathogens. The long-term expected outcomes are 1) the establishment of new synthetic methodology for systematic medicinal chemistry SAR-based exploration of the aminoglycoside chemical space and 2) the discovery of new aminoglycoside structural motifs with improved activity against resistant bacteria (e.g., AME, RMT- mediated resistance). The underlying hypothesis that guides our approach is the assumption that there are many carbohydrate structures that remain undiscovered due to the synthetic limitations of traditional carbohydrate and semi-synthetic approaches. In contrast, our total de novo synthetic approach enables the installation of a much broader range of carbohydrates in a stereochemically selective manner. Examples of structural variations that will be explored are aminoglycosides with rare aminosugar, linear sugar, and 2- deoxystreptamine (2-DOS) substitutions that are designed to evade known aminoglycoside resistance mechanisms.


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: 2023 ( Subtotal = $757,156 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	7/6/2023	NON-COMPETING CONTINUATION	$757,156
														Subtotal = $757,156

Issue Date FY: 2022 ( Subtotal = $765,318 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	8/2/2022	NON-COMPETING CONTINUATION	$765,318
														Subtotal = $765,318

Issue Date FY: 2021 ( Subtotal = $772,551 )
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	7/6/2021	NON-COMPETING CONTINUATION	$772,551
														Subtotal = $772,551

Issue Date FY: 2020 ( Subtotal = $815,399 )
2020	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	8/20/2020	NEW	$815,399
														Subtotal = $815,399

Grand Total All Awards = $3,110,424

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De Novo Synthesis, and Functional and Structural Characterization of Novel Aminoglycoside Analogues to Bypass Resistance Mechanisms and Optimize Selectivity

Award Number: R01AI154860

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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