<jats:title>ABSTRACT</jats:title> <jats:p> Natural products produced by microorganisms are important starting compounds for drug discovery. Secondary metabolites, including antibiotics, have been isolated from different <jats:italic>Streptomyces</jats:italic> species. The production of these metabolites depends on the culture conditions. Therefore, the development of a new culture method can facilitate the discovery of new natural products. Here, we show that mycolic acid-containing bacteria can influence the biosynthesis of cryptic natural products in <jats:italic>Streptomyces</jats:italic> species. The production of red pigment by <jats:italic>Streptomyces lividans</jats:italic> TK23 was induced by coculture with <jats:italic>Tsukamurella pulmonis</jats:italic> TP-B0596, which is a mycolic acid-containing bacterium. Only living cells induced this pigment production, which was not mediated by any substances. <jats:italic>T</jats:italic> . <jats:italic>pulmonis</jats:italic> could induce natural-product synthesis in other <jats:italic>Streptomyces</jats:italic> strains too: it altered natural-product biosynthesis in 88.4% of the <jats:italic>Streptomyces</jats:italic> strains isolated from soil. The other mycolic acid-containing bacteria, <jats:italic>Rhodococcus erythropolis</jats:italic> and <jats:italic>Corynebacterium glutamicum</jats:italic> , altered biosynthesis in 87.5 and 90.2% of the <jats:italic>Streptomyces</jats:italic> strains, respectively. The coculture broth of <jats:italic>T</jats:italic> . <jats:italic>pulmonis</jats:italic> and <jats:italic>Streptomyces endus</jats:italic> S-522 contained a novel antibiotic, which we named alchivemycin A. We concluded that the mycolic acid localized in the outer cell layer of the inducer bacterium influences secondary metabolism in <jats:italic>Streptomyces</jats:italic> , and this activity is a result of the direct interaction between the mycolic acid-containing bacteria and <jats:italic>Streptomyces</jats:italic> . We used these results to develop a new coculture method, called the combined-culture method, which facilitates the screening of natural products.