How tuberculosis bacteria evolved two different signaling systems

Bacteria use small chemical signals called cyclic dinucleotides (CDNs) to control crucial life processes. Two of these signals, cyclic di-AMP (c-di-AMP) and cyclic di-GMP (c-di-GMP), influence things like cell wall synthesis, biofilm formation, antibiotic resistance, stress responses and virulence. These pathways are especially important in major human pathogens such as Mycobacterium tuberculosis, and they may also help explain why environmental relatives, known as non-tuberculous mycobacteria (NTM), are increasingly found causing disease. To investigate how CDN signaling evolved across the group that includes tuberculosis bacteria, researchers led by Kamakshi Sureka carried out a broad comparative genomic analysis across members of the Mycobacteriaceae family. Their work focused on genes that make and break these signals, including the c-di-AMP synthase disA and the enzymes that degrade CDNs, such as PDE and AtaC, as well as the components of the c-di-GMP system: diguanylate cyclases (DGCs) and phosphodiesterases (PDEs). By comparing gene presence, copy number and sequence variation across species, the team set out to map which signaling systems are universal and which have changed as different mycobacterial lineages adapted to new environments.

Using comparative genomic and evolutionary analyses, the study examined how the genes for CDN signaling are distributed across mycobacterial genomes. The researchers found that disA, the gene that synthesizes c-di-AMP, is present as a single copy in nearly all mycobacterial genomes they examined, with the notable exception of species in the genus Mycolicibacter. In contrast, the enzymes that degrade c-di-AMP are more variable: the phosphodiesterases PDE and AtaC do not follow a single pattern, and pathogenic mycobacteria showed a tendency to retain PDE more often than AtaC. The c-di-GMP pathway proved much less uniform. Genes encoding diguanylate cyclases (DGCs) and the corresponding phosphodiesterases (PDEs) showed striking differences in presence or absence and in their domain architectures across the Mycobacteriaceae family. These patterns are consistent with multiple, independent gene gain and loss events during evolution, frequently accompanied by the acquisition of accessory domains. Evolutionary tests indicated that disA is under strong purifying selection, similar to core housekeeping genes, while pde shows relatively low diversity—supporting the idea that c-di-AMP signaling is highly conserved.

Taken together, the findings reveal a sharp evolutionary split in CDN signaling within mycobacteria. c-di-AMP, produced by disA and regulated by PDE-family enzymes, appears to be an indispensable and conserved element of core mycobacterial physiology. By contrast, the c-di-GMP signaling system is patchy and flexible, varying in gene content and domain structure in ways that suggest it helps different species adapt to specific environmental niches. For researchers and public health specialists, this distinction matters: a conserved system like c-di-AMP could underlie essential cellular functions common to both pathogens and environmental species, while variability in c-di-GMP may help explain how some environmental mycobacteria become opportunistic pathogens. The work therefore provides a framework for future studies that aim to link specific signaling architectures to traits such as virulence, antibiotic resistance and environmental persistence, and it highlights the importance of evolutionary context when studying bacterial signaling pathways in the Mycobacterium genus.