A silent sulfonamide-resistant microbial world: The curious case of missing DHPS in candidate phyla radiation.

Candidate phyla radiation (CPR) microbes exhibit minimal genomes, episymbiotic/parasitic lifestyles, and metabolic dependencies on host cells. In this study, we look for the presence of dihydropteroate synthase (DHPS) and dihydrofolate reductase, key folate biosynthesis enzymes targeted by sulfonamides and trimethoprim, respectively. Using bioinformatic computational methods, analysis of 12 535 (complete and non-complete) CPR genomes revealed the presence of dihydrofolate reductase enzyme in 54% of them, while DHPS was detected in only 6%, suggesting an inherent absence of the folP gene (corresponding to the DHPS). Structural and functional validation confirmed the lack of DHPS activity. These findings indicate an intrinsic resistance to sulfonamides in CPR microbes, raising questions about their adaptation and persistence in antibiotic-rich environments.