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• W4282942938 abstract "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. In addition, these results indicate that primary metabolism may be a direct target for inhibition via chemical interference in competitive microbial interactions. IMPORTANCE Many antibiotics were originally discovered from microbes. However, in recent decades, resistance to current treatments has risen, while novel antibiotic discovery has become increasingly challenging. Thus, there is a need to develop new strategies to find novel antimicrobials. Here, we incorporated three levels of innovation into a single, simple discovery pipeline: focusing on understudied bacteria with a high potential for producing antibiotics, growing these bacteria in binary microbial interactions, and screening for activity against a multidrug-resistant bacterium. This led us to discover a family of antimicrobials that we call the dynaplanins, which are synthesized by genes that were not detected by typical prediction algorithms. We found that dynaplanins likely block the function of one of three related enzymes called 2-oxo acid dehydrogenases, which are vital to cellular metabolism. Overall, our strategy based on bacterial competition led to discovery of a novel antibiotic that inhibits the ability to metabolize nutrients." @default.
• W4282942938 created "2022-06-16" @default.
• W4282942938 creator A5007797750 @default.
• W4282942938 creator A5012873471 @default.
• W4282942938 creator A5055311146 @default.
• W4282942938 creator A5074076287 @default.
• W4282942938 creator A5081117163 @default.
• W4282942938 creator A5084797883 @default.
• W4282942938 date "2022-06-28" @default.
• W4282942938 modified "2023-10-13" @default.
• W4282942938 title "Harnessing Rare Actinomycete Interactions and Intrinsic Antimicrobial Resistance Enables Discovery of an Unusual Metabolic Inhibitor" @default.
• W4282942938 cites W139194249 @default.
• W4282942938 cites W1528663691 @default.
• W4282942938 cites W1827349067 @default.
• W4282942938 cites W193034086 @default.
• W4282942938 cites W1969925958 @default.
• W4282942938 cites W1971439989 @default.
• W4282942938 cites W1979973356 @default.
• W4282942938 cites W1985748618 @default.
• W4282942938 cites W1986439031 @default.
• W4282942938 cites W1996658127 @default.
• W4282942938 cites W1999742995 @default.
• W4282942938 cites W2008343440 @default.
• W4282942938 cites W2012251902 @default.
• W4282942938 cites W2014680208 @default.
• W4282942938 cites W2019494456 @default.
• W4282942938 cites W2025184785 @default.
• W4282942938 cites W2026252608 @default.
• W4282942938 cites W2026572950 @default.
• W4282942938 cites W2032937768 @default.
• W4282942938 cites W2039467082 @default.
• W4282942938 cites W2040285328 @default.
• W4282942938 cites W2041537722 @default.
• W4282942938 cites W2044718961 @default.
• W4282942938 cites W2062314447 @default.
• W4282942938 cites W2064536357 @default.
• W4282942938 cites W2067844277 @default.
• W4282942938 cites W2069852546 @default.
• W4282942938 cites W2071451446 @default.
• W4282942938 cites W2073504782 @default.
• W4282942938 cites W2078598169 @default.
• W4282942938 cites W2082584140 @default.
• W4282942938 cites W2083025941 @default.
• W4282942938 cites W2095046898 @default.
• W4282942938 cites W2095753590 @default.
• W4282942938 cites W2099202202 @default.
• W4282942938 cites W2101760102 @default.
• W4282942938 cites W2111858899 @default.
• W4282942938 cites W2124135331 @default.
• W4282942938 cites W2131256962 @default.
• W4282942938 cites W2136520405 @default.
• W4282942938 cites W2151977734 @default.
• W4282942938 cites W2156721589 @default.
• W4282942938 cites W2166801599 @default.
• W4282942938 cites W2178043251 @default.
• W4282942938 cites W2293778553 @default.
• W4282942938 cites W2470052926 @default.
• W4282942938 cites W2515810634 @default.
• W4282942938 cites W2547632626 @default.
• W4282942938 cites W2574318393 @default.
• W4282942938 cites W2594924041 @default.
• W4282942938 cites W2600203898 @default.
• W4282942938 cites W2606692795 @default.
• W4282942938 cites W2609970963 @default.
• W4282942938 cites W2614151742 @default.
• W4282942938 cites W2618350855 @default.
• W4282942938 cites W2623609424 @default.
• W4282942938 cites W2745396386 @default.
• W4282942938 cites W2769012525 @default.
• W4282942938 cites W2770076272 @default.
• W4282942938 cites W2772047293 @default.
• W4282942938 cites W2782147921 @default.
• W4282942938 cites W2788228074 @default.
• W4282942938 cites W2798224715 @default.
• W4282942938 cites W2805007008 @default.
• W4282942938 cites W2806850877 @default.
• W4282942938 cites W2807727258 @default.
• W4282942938 cites W2808840038 @default.
• W4282942938 cites W2892049504 @default.
• W4282942938 cites W2893128668 @default.
• W4282942938 cites W2893448478 @default.
• W4282942938 cites W2901215603 @default.
• W4282942938 cites W2917207851 @default.
• W4282942938 cites W2920706451 @default.
• W4282942938 cites W2942346949 @default.
• W4282942938 cites W2951011311 @default.
• W4282942938 cites W2962917655 @default.
• W4282942938 cites W2970567433 @default.
• W4282942938 cites W2973437617 @default.
• W4282942938 cites W2977016306 @default.
• W4282942938 cites W2980278798 @default.
• W4282942938 cites W2981466908 @default.
• W4282942938 cites W2990471452 @default.
• W4282942938 cites W2990613596 @default.
• W4282942938 cites W3008003852 @default.
• W4282942938 cites W3033107086 @default.
• W4282942938 cites W3034695813 @default.
• W4282942938 cites W3080548634 @default.
• W4282942938 cites W3119125484 @default.
• W4282942938 cites W3122549843 @default.

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