NIH grant: Strepothricin gulosamine derivatization to enhance selectivity against gram-negative ESKAPE pathogens (1R21AI202366-01)

retained text

NIH grant 1R21AI202366-01: Strepothricin gulosamine derivatization to enhance selectivity against gram-negative ESKAPE pathogens
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Roman  Manetsch. Award: $261675.
Start: 2026-07-17T00:00:00.
Project Summary
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.

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