Bio-guided discovery of antibacterial metabolites from <i>Penicillium chrysogenum</i>

Bio-guided isolation from the Red Sea-derived <i>Penicillium chrysogenum</i> yielded two new metabolites, 15-deoxy-15-amino-citreohybridonol (<b>6</b>) and chrysogenotoxin (<b>7</b>), alongside five known compounds: emodin (<b>1</b>), chrysophanol (<b>2</b>), <i>bis</i>(2-ethylhexyl) phthalate (<b>3</b>), haenamindole (<b>4</b>), and citreorosein (<b>5</b>). Compound <b>6</b> exhibited broad-spectrum antibacterial activity against both Gram-positive (MIC: 0.31-0.62 μM; MBC: 0.31-0.62 μM) and Gram-negative bacteria (MIC: 0.15-1.25 μM; MBC: 0.62-2.5 μM). Compound <b>7</b> showed potent bactericidal activity against Gram-negative bacteria (MIC: 0.07-0.31 μM; MBC: 0.15-0.62 μM) with MBC/MIC ≤ 4, while compound <b>4</b> selectively inhibited <i>S. pneumoniae</i> (MIC: 0.31 μM; MBC: 0.62 μM). Compounds <b>4</b>, <b>6</b>, and <b>7</b> exhibited low cytotoxicity towards human intestinal epithelial cells (HIEC-6). Molecular docking studies targeting the NDM-1 β-lactamase identified compounds <b>4</b>, <b>6</b>, and <b>7</b> as potential inhibitors of New Delhi metallo-β-lactamase-1 (NDM-1). Molecular dynamics simulations confirmed the structural stability of <b>7</b> within the NDM-1 active site. Chrysogenotoxin (<b>7</b>) was suggested as a promising antibacterial candidate against antibiotic-resistant pathogens.