Co-targeting Metabolic Neighbours Constraints Bacterial Adaptive Evolution.

Dwipanjan Sanyal, Yun-Ti Chen, Carl Ho, Arthur McClelland, Sourav Chowdhury, Eugene I Shakhnovich

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Article in bioRxiv : the preprint server for biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

Authors and funding

6 authors.

Dwipanjan SanyalDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.

Yun-Ti ChenDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.

Carl HoDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.

Arthur McClellandCenter for Nanoscale Systems, Faculty of Arts and Sciences, Harvard University, Cambridge, MA, USA.

Sourav ChowdhuryDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.

Eugene I ShakhnovichDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.

Funding

Biophysical foundations of evolutionary dynamicsR35GM139571 · NIGMS · HARVARD UNIVERSITY · PI SHAKHNOVICH, EUGENE I · 2021 to 2025

$3.9M

NIGMS NIH HHS R35 GM139571

6 · The paper itself

Abstract

Antibiotic resistance often arises through genetic changes that reduce drug susceptibility, with mutation representing one of the primary mechanisms. Here, we report a dual targeting strategy that restricts these escape routes by simultaneously inhibiting two metabolic neighbours in folate biosynthesis pathway. To establish a general framework for limiting adaptive escape in bacteria, we screened the folate pathway to identify enzymes with shared conserved structural features. This analysis identified dihydroneopterin aldolase (folB) and dihydroneopterin triphosphate 2'-epimerase (folX) as optimal dual targets due to their shared pocket architecture and their roles early in the folate pathway. We then screened a large chemical space of FDA-approved small molecules to identify candidates predicted to bind both folB and folX, followed by experimental validation. We identified Arbutin showing the strongest growth inhibition in

Indexed as

Arbutinbacterial adaptationdrug repurposingdrug resistancedrug screeningevolutionevolutionary constraintFolate biosynthesis

Identifiers

PMID42282799

DOI10.64898/2026.06.04.729935

PMCPMC13251999

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