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Decreasing discovery rates and increasing resistance have underscored the need for novel therapeutic options to treat Mycobacterium tuberculosis infection. Here, we screen extracts from previously uncultured soil microbes for specific activity against Mycobacterium tuberculosis, identifying three novel compounds. We further define the mechanism of action of one compound, amycobactin, and demonstrate that it inhibits protein secretion through the Sec translocation machinery., Mycobacterium tuberculosis, which causes tuberculosis (TB), is estimated to infect one-third of the world’s population. The overall burden and the emergence of drug-resistant strains of Mycobacterium tuberculosis underscore the need for new therapeutic options against this important human pathogen. Our recent work demonstrated the success of natural product discovery in identifying novel compounds with efficacy against Mycobacterium tuberculosis. Here, we improve on these methods by combining improved isolation and Mycobacterium tuberculosis selective screening to identify three new anti-TB compounds: streptomycobactin, kitamycobactin, and amycobactin. We were unable to obtain mutants resistant to streptomycobactin, and its target remains to be elucidated. We identify the target of kitamycobactin to be the mycobacterial ClpP1P2C1 protease and confirm that kitamycobactin is an analog of the previously identified compound lassomycin. Further, we identify the target of amycobactin to be the essential protein secretion pore SecY. We show further that amycobactin inhibits protein secretion via the SecY translocon. Importantly, this inhibition is bactericidal to nonreplicating Mycobacterium tuberculosis. This is the first compound, to our knowledge, that targets the Sec protein secretion machinery in Mycobacterium tuberculosis. This work underscores the ability of natural product discovery to deliver not only new compounds with activity against Mycobacterium tuberculosis but also compounds with novel targets.

Controlling the optical properties of conjugated materials, especially their bandgaps, is critical to nearly all of applications of these materials. The most prevalent strategy involves changes to the structures of conjugated backbones, while side chains are generally reserved for imparting solubility. This paper, using a series of donor–acceptor conjugated oligo- and poly(arylene–ethynylene)s that have terephthalate units as the electron-deficient unit, demonstrates examples of how the structures of side chains that are not formally part of the conjugated backbone can have significant effects on bandgaps of these materials. In organic solution, changing alkoxy substituents on the terephthalate unit yields changes in absorbance onsets of, in some cases, greater than 20 nm; the position of absorbance spectra of these materials correlates with the Taft σ* values of the ester alkoxy groups, consistent with the side chains inductively altering the electron-accepting nature of the terephthalate ring. This stru...