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Harnessing rare actinomycete interactions and intrinsic antimicrobial resistance enables discovery of a metabolic inhibitor with an unusual mode of action


Bacterial natural products have historically been a deep source of new medicines, but their slowed discovery in recent decades has put a premium on developing strategies that enhance the likelihood of capturing novel compounds. Here, we used a straightforward approach that capitalizes on the interactive ecology of ‘rare’ actinomycetes. Specifically, we screened for interactions that triggered the production of antimicrobials that inhibited the growth of a bacterial strain with exceptionally diverse natural antimicrobial resistance. This strategy led to the discovery of a family of antimicrobials we term the dynaplanins. Heterologous expression enabled identification of the dynaplanin biosynthetic gene cluster, which was missed by typical algorithms for natural product gene cluster detection. Genome sequencing of partially resistant mutants revealed a 2-oxo acid dehydrogenase E2 subunit as the likely molecular target of the dynaplanins, and this finding was supported by computational modeling of the dynaplanin scaffold within the active site of this enzyme. Thus, this simple strategy, which leverages microbial interactions and natural antibiotic resistance, can enable discovery of molecules with unique antimicrobial activity. We aim to adapt this strategy into a microfluidics platform to improve its throughput. In this regard, we have established a prototype of this device in its final stages, though some minor adjustments need to be made before undertaking a full screen. Overall, these results highlight the strength of this screening strategy and indicate that primary metabolism may be a direct target for inhibition via chemical interference in competitive microbial interactions.

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