New approaches are still needed to fully explore the biosynthetic potential of microbes. We recently devised a <i>melC</i> reporter-guided fermentation media screening approach for targeted activation of cryptic gene clusters. Using this approach, we successfully activated the expression of the <i>hcl</i> gene cluster in <i>Streptomyces</i> sp. LZ35 and discovered a novel polyene macrolide hexacosalactone A (<b>1</b>).