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Development of next generation spectinomycin analogs that evade modifying enzyme-based resistance and show enhanced potency against multidrug-resistant pathogens.

Award Number: R21AI199146
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Development of next generation spectinomycin analogs that evade modifying enzyme-based resistance and show enhanced potency against multidrug-resistant pathogens. - Project Summary Multi-drug resistance is rapidly emerging among carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii. With increasing frequency, these pathogens often prove untreatable or treatable only with toxic antimicrobials. Therefore, the CDC now categorizes such organisms in their top antibiotic resistance threat level. New anti-infective strategies are urgently needed. Spectinomycin is a novel tricyclic aminocyclitol antibiotic approved for treatment of N. gonorrhoeae. It has an excellent safety profile in humans. Unlike other aminoglycoside antibiotics, it is neither ototoxic nor renal toxic. It also remains active in the presence of widely circulating ribosomal methylases. However, it is covalently inactivated at a single site by circulating adenylases. It also does not efficiently penetrate the outer membrane of gram-negative ESKAPE pathogens; and, therefore, these pathogens are relatively resistant to achievable drug levels. However, experiments performed in combination with membrane-permeabilizing agents, strains with defects in the outer membrane, and with in vitro translation extracts indicate that gram-negative pathogens are susceptible to this antibiotic if outer membrane penetration is facilitated. Recently, molecular properties that enhance penetrance into gram-negatives have been defined. Based on intrinsically compelling properties of spectinomycin, we propose to use structure- and molecular property-guided de novo asymmetric glycochemistry in combination with streptamine semi-synthesis in the design of spectinomycin analogs with enhanced penetrance and that escape modification by aad-class adenylases and thereby evade circulating resistance. The underlying goal will be to identify analogs that have broad-spectrum activity against resistant gram-negative pathogens and fill a critical unmet medical need. There are no previously published modern efforts along the lines proposed targeting gram-negative ESKAPE pathogens, and, therefore, the proposed work is both novel and innovative. Importantly, the analogs will be profiled in a series of complementary functional studies. These will include both in vitro and in vivo measurements that will distinguish effects of penetrance and intrinsic translational inhibition; activity spectrum studies; assessment of metabolic stability; and proof-of-principle in vivo efficacy experiments that together will inform future intensive exploration of lead candidates. The near-term goal of this two-year, exploratory R21 proposal is to identify tractable, potent, broad-spectrum spectinomycin analogs worthy of further exploration.


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 = $493,865 )
2026	2026	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	6/30/2026	NEW	$493,865
														Subtotal = $493,865

Grand Total All Awards = $493,865

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Development of next generation spectinomycin analogs that evade modifying enzyme-based resistance and show enhanced potency against multidrug-resistant pathogens.

Award Number: R21AI199146

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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