With access to psychotrimine provided by the recently reported gram scale total synthesis,6 we sought to examine the potential antibacterial activity of this unique indole alkaloid. We first screened a variety of bacteria for sensitivity to psychotrimine according to CLSI guidelines.7 No activity was observed against Pseudomonas aeruginosa PA01 or Klebsiella pneumoniae ATCC 43816 up to 128 μg ml−1. We observed mild activity against Escherichia coli MG1655, inhibiting growth with an MIC of 128 μg ml−1. Polymyxin B nonapeptide does not sensitize E. coli to psychotrimine, suggesting that the absence of activity against Gram-negative bacteria is not the result of limited outer membrane penetration. In contrast, more significant activity against Gram-positive bacteria was observed. Psychotrimine is reasonably active against Bacillus subtilis 168, Streptococcus agalactiae COH1 and S. pyogenes 5448, inhibiting growth of each with an MIC of 16 μg ml−1, and moderately active against Staphylococcus epidermidis RP62A and S. aureus 8325, inhibiting growth with an MIC of 32 and 64 μg ml−1, respectively.

To begin to understand the mechanism by which psychotrimine kills Gram-positive bacteria, we attempted to isolate resistant mutants of B. subtilis and S. aureus. However, after plating >5 × 109 c.f.u. on Mueller-Hinton agar plates containing 2 × MIC psychotrimine, no viable colonies could be recovered. Moreover, serial passage of B. subtilis cells in sub-MIC concentrations of psychotrimine for 50 generations also failed to yield resistant colonies. These data suggest that resistant mutants, at least in B. subtilis and S. aureus, are extremely rare. Such low levels of resistance are common with a variety of mechanisms, including membrane disruption, which is also consistent with the positively charged lipophilic structure of psychotrimine.8

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