Evolution of beta-lactam biosynthesis genes and recruitment of trans-acting factors

Penicillins and cephalosporins belong chemically to the group of beta-lactam antibiotics. The formation of hydrophobic penicillins has been reported in fungi only, notably Penicillium chrysogenum and Emericella nidulans, whereas the hydrophilic cephalosporins are produced by both fungi, e.g., Acremonium chrysogenum (cephalosporin C), and bacteria. The producing bacteria include Gram-negatives and Gram-positives, e.g. Lysobacter lactamdurans (cephabacins) and Streptomyces clavuligerus (cephamycin C), respectively. For a long time the evolutionary origin of beta-lactam biosynthesis genes in fungi has been discussed. As often, there are arguments for both hypotheses, i.e., horizontal gene transfer from bacteria to fungi versus vertical descent. There were strong arguments in favour of horizontal gene transfer, e.g., fungal genes were clustered or some genes lack introns. The recent identification and characterisation of cis-/trans-elements involved in the regulation of the beta-lactam biosynthesis genes has provided new arguments in favour of horizontal gene transfer. In contrast to the bacterium S. clavuligerus, all regulators of fungal beta-lactam biosynthesis genes represent wide-domain regulators which were recruited to also regulate the beta-lactam biosynthesis genes. Moreover, the fungal regulatory genes are not part of the gene cluster. If bacterial regulators were co-transferred with the gene cluster from bacteria to fungi, most likely they would have been non-functional in eukaryotes and lost during evolution. Alternatively, it is conceivable that only a part of the beta-lactam biosynthesis gene cluster was transferred to some fungi, e.g., the acvA and ipnA gene without a regulatory gene.