RT Journal Article SR Electronic(1) A1 Gomez-Escribano, Juan P. A1 Martín, Juan F. A1 Hesketh, A. A1 Bibb, M. J. A1 Liras, P.YR 2008 T1 Streptomyces clavuligerus relA-null mutants overproduce clavulanic acid and cephamycin C: negative regulation of secondary metabolism by (p)ppGpp JF Microbiology, VO 154 IS 3 SP 744 OP 755 DO https://doi.org/10.1099/mic.0.2007/011890-0 PB Microbiology Society, SN 1465-2080, AB The (p)ppGpp synthetase gene, relA, of Streptomyces clavuligerus was cloned, sequenced and shown to be located in a genomic region that is highly conserved in other Streptomyces species. relA-disrupted and relA-deleted mutants of S. clavuligerus were constructed, and both were unable to form aerial mycelium or to sporulate, but regained these abilities when complemented with wild-type relA. Neither ppGpp nor pppGpp was detected in the S. clavuligerus relA-deletion mutant. In contrast to another study, clavulanic acid and cephamycin C production increased markedly in the mutants compared to the wild-type strain; clavulanic acid production increased three- to fourfold, while that of cephamycin C increased about 2.5-fold. Complementation of the relA-null mutants with wild-type relA decreased antibiotic yields to approximately wild-type levels. Consistent with these observations, transcription of genes involved in clavulanic acid (ceaS2) or cephamycin C (cefD) production increased dramatically in the relA-deleted mutant when compared to the wild-type strain. These results are entirely consistent with the growth-associated production of both cephamycin C and clavulanic acid, and demonstrate, apparently for the first time, negative regulation of secondary metabolite biosynthesis by (p)ppGpp in a Streptomyces species of industrial interest., UL https://www.microbiologyresearch.org/content/journal/micro/10.1099/mic.0.2007/011890-0