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Rifamycin W, the most predominant intermediate in the biosynthesis of rifamycin, needs to undergo polyketide backbone rearrangement to produce rifamycin B via an oxidative cleavage of the C-12/C-29 double bond. However, the mechanism of this putative oxidative cleavage has not been characterized yet. Rif-Orf5 (a putative cytochrome P450 monooxygenase) was proposed to be involved in the cleavage of this olefinic moiety of rifamycin W. In this study, the mutant strain <i>Amycolatopsis mediterranei</i> S699 Δ<i>rif-orf5</i> was constructed by in-frame deleting the <i>rif</i>-<i>orf5</i> gene to afford thirteen rifamycin W congeners (<b>1</b>–<b>13</b>) including seven new ones (<b>1</b>–<b>7</b>). Their structures were elucidated by extensive analysis of 1D and 2D NMR spectroscopic data and high-resolution ESI mass spectra. Presumably, compounds <b>1</b>–<b>4</b> were derivatized from rifamycin W via C-5/C-11 retro-Claisen cleavage, and compounds <b>1</b>–<b>3</b>, <b>9</b> and <b>10</b> featured a hemiacetal. Compounds <b>5</b>–<b>7</b> and <b>11</b> showed oxygenations at various sites of the <i>ansa</i> chain. In addition, compounds <b>1</b>–<b>3</b> exhibited antibacterial activity against <i>Staphylococcus aureus</i> with minimal inhibitory concentration (MIC) values of 5, 40 and 0.5 µg/mL, respectively. Compounds <b>1</b> and <b>3</b> showed modest antiproliferative activity against HeLa and Caco-2 cells with half maximal inhibitory concentration (IC₅₀) values of about 50 µM.