“…Indeed, the integration of the tools of “classical” and “modern” approaches enables the researchers to stack multiple complex phenotypes [22] . For CA overproduction, the genetic and metabolic engineering approaches involving altering expression levels of biosynthetic or regulatory genes, increasing precursor flow into the pathway or eliminating competing reactions by oriented modifications have been applied mostly to the laboratory strains of S. clavuligerus , as summarized in Table S1 [11] , [12] , [13] , [23] , [24] , [25] , [26] , [27] , [28] , [29] . Because standard strains are able to produce only limited amounts of secondary metabolites, application of knowledge-based gene manipulations in industrial strains derived from random mutagenesis and selection might provide more productive strains [16] , [30] .…”