Strepothricin gulosamine derivatization to enhance selectivity against gram-negative eskape pathogens

The National Institute of Allergy and Infectious Diseases awarded Northeastern University $261,675 on July 17, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to conduct exploratory research on streptothricin derivatization against gram-negative ESKAPE pathogens.

The research explores synthetic modification of the gulosamine sugar moiety of streptothricins—antibiotics discovered over 70 years ago that inhibit bacterial protein translation. Preliminary data demonstrates that streptothricins show 40-fold selectivity for prokaryotic ribosomes compared with eukaryotic ribosomes and exhibit activity in vitro against carbapenem-resistant Enterobacterales; murine thigh infection models with pandrug-resistant K. pneumoniae showed near-sterilizing response to a single streptothricin F dose at 50 mg/kg with no observable toxicity. The award funds synthetic exploration of structural variants around the gulosamine sugar to enhance prokaryotic potency, selectivity, and activity spectrum while advancing understanding of structure-activity relationships. Work occurs in Boston, Massachusetts, with a period of performance through June 30, 2028. The assistance type is a Project Grant (R21).

Abstract

The rapid emergence of antimicrobial resistance presents a significant challenge for the treatment of bacterial infections. Multidrug-resistant gram-negative infections are of particular concern. We are clearly in need of several new gram-negative agents which can diversify our antimicrobial portfolio. Streptothricins were identified over 70 years ago and inhibit protein translation with extensive protein miscoding as a result of their novel mode of binding. We found that streptothricins are highly active in vitro against carbapenem-resistant enterobacterales. In murine thigh infection model experiments with the pandrug-resistant k. Pneumoniae nevada strain, a single dose of streptothricin f (s-f) was almost sterilizing at 50 MG/KG with no observable toxicity. In vitro translation experiments indicate that streptothricins show a 40X fold selectivity for prokaryotic ribosomes compared with eukaryotic cytosolic ribosomes. Streptothricins contain three moieties: a streptolidine, a gulosamine sugar, and a single β-lysine or poly-β-lysine chain of varying length (s-f has a single -lysine). Based on prior literature and our structural modeling, we hypothesize that the gulosamine sugar derivatization provides a compelling opportunity to further increase prokaryotic potency and selectivity and broaden activity spectrum. Therefore, in this exploratory R21 grant, we propose synthetic exploration of structural space around the gulosamine sugar to explore opportunities to enhance properties and further elucidate structure-activity relationships. Supporting the premise of this exploratory R21 proposal, we have generated compelling preliminary data that clearly demonstrates the feasibility of a novel DE novo synthesis for streptothricin f, enabling facile replacement of the sugar moiety to produce both natural and unnatural streptothricin analogs. Our proposed work will be approached in one specific aim that combines medicinal chemistry and biological characterization of analogs. Structure-activity relationship (SAR) studies on the sugar moiety have not been performed previously. Therefore, this high risk, high reward proposal will provide the field with significant insight into the potential for sugar moiety analogs to advance drug-like properties of the streptothricin scaffold.