Bacillomycin D is a nonribosomal peptide produced by Bacillus amyloliquefaciens fmbJ. In this study, the biosynthesis of bacillomycin D was mediated by replacing the intermodule donor, acceptor, and communication-mediating (COM) domain pairs and introducing the COM domain between the surfactin subunits. Both the homologous donor and the COM domain pair replacement strains eliminated the selective barrier of the original COM domain pair to a certain extent, resulting in a more flexible hybrid biosynthesis system that provides simultaneous biosynthesis of different lipopeptide products. The synthesis of bacillomycin D in the homologous acceptor replacement strains was barely affected. The COM domains between the surfactin subunits cannot establish efficient communication between the bacillomycin D modules. In conclusion, the COM domains compatibility between the bacillomycin D modules are extremely strong, and the conserved amino acid residues in the acceptor domain are an important part of module–module interactions and efficient communication during bacillomycin D synthesis.