Inactivation of a transcriptional repressor during empirical improvement of the tylosin producer, streptomyces fradiae

Remarkably few changes of significance seem to have occurred within the tylosin-biosynthetic gene cluster of Streptomyces fradiae during an extensive portion of the empirical strain improvement programme carried out at Lilly Research Laboratories over many years. None of the promoters for polyketide synthase (PKS) genes or for regulatory elements changed within this part of the lineage, nor were any mutations detected in other tyl promoters, although the full set was probably not analysed. Of five regulatory genes within the tyl cluster, only tylQ was altered, having undergone a single point mutation that inactivated its product (a transcriptional repressor). Also unchanged was a gene with unassigned function. Since point mutations affecting antibiotic-biosynthetic enzymes are unlikely to have played a major role in empirical strain improvement, enhanced tylosin production levels appear to have resulted, in large measure, from uncharacterized mutations occurring outside the tyl cluster.