| Summary: | Small molecules that can restore the action of legacy antibiotics toward drug-resistant bacteria represent an area of ongoing research interest. We have previously reported indole-3-glyoxylamido and indole-3-acetamido-polyamine conjugates that exhibit intrinsic activity toward bacterial and fungal species, and the ability to enhance the action of doxycycline toward the Gram-negative bacteria <i>Pseudomonas aeruginosa</i>; however, these desirable activities were commonly associated with unfavorable cytotoxicity and/or red blood cell hemolytic properties. In this paper, we report the synthesis and biological investigation of a new class of α,ω-di(indole-3-carboxamido)polyamine derivatives, leading to the identification of several analogues that exhibit antimicrobial- and antibiotic-potentiating activities without detectable cytotoxic or hemolytic properties. 5-Bromo-substituted indole analogues <b>3</b> and <b>12</b>–<b>18</b> were generally more broad-spectrum in their activity than others in the set, with <b>13b</b> (polyamine PA-3-6-3) being particularly notable for its anti-<i>Staphylococcus aureus</i>, <i>Acinetobacter baumannii</i>, and <i>Cryptococcus neoformans</i> activities (MIC ≤ 0.28 µM). The same analogue also restored the action of doxycycline toward <i>P. aeruginosa</i> with a 21-fold enhancement, while the corresponding 5-bromo-indole-3-carboxamide-PA3-7-3 analogue was able to enhance the action of both doxycycline and erythromycin toward <i>P. aeruginosa</i> and <i>Escherichia coli</i>, respectively. The analogue <b>13b</b> was capable of disrupting the bacterial membrane of both <i>S. aureus</i> and methicillin-resistant <i>S. aureus</i> (MRSA) and the outer membrane of <i>P. aeruginosa</i>, suggesting that membrane perturbation could be a mechanism of action of both intrinsic antimicrobial activities and antibiotic potentiation.
|
|---|