Involvement of nitrogen-containing compounds in beta-lactam biosynthesis and its control

Biosynthesis of beta-lactam antibiotics by fungi and actinomycetes is markedly affected by compounds containing nitrogen. The different processes employed by the spectrum of microbes capable of making these valuable compounds are affected differently by particular compounds. Ammonium ions, except at very low concentrations, exert negative effects via nitrogen metabolite repression, sometimes involving the nitrogen regulatory gene nre. Certain amino acids are precursors or inducers, whereas others are involved in repression and, in certain cases, as inhibitors of biosynthetic enzymes and of enzymes supplying precursors. The most important amino acids from the viewpoint of regulation are lysine, methionine, glutamate and valine. Surprisingly, diamines such as diaminopropane, putrescine and cadaverine induce cephamycin production by actinomycetes. In addition to penicillins and cephalosporins made by fungi and cephamycins made by actinomycetes, other beta-lactams are made by actinomycetes and unicellular bacteria. These include clavams (e.g., clavulanic acid), carbapenems (e.g., thienamycin), nocardicins and monobactams. Here also, amino acids are precursors and inhibitors, but only little is known about regulation. In the case of the simplest carbapenem made by unicellular bacteria, i.e., 1-carba-2-em-3-carboxylic acid, quorum sensors containing homoserine lactone are inducers.