Phage-Derived Antimicrobial Strategies Against Treponema pallidum: Genomic Evidence, Biological Barriers, and Translational Roadmap

Syphilis is a systemic sexually transmitted infection caused by Treponema pallidum subsp. pallidum. Despite effective penicillin-based therapy, it remains a major public health challenge due to ongoing transmission, latent infection, congenital disease, and the lack of a licensed vaccine. While the resurgence of bacteriophage research has stimulated interest in alternative antimicrobials for sexually transmitted infections, direct extrapolation of classical lytic phage therapy to T. pallidum is premature. This pathogen is experimentally demanding, grows slowly, lacks validated lytic phages, and possesses an unusual outer membrane with sparse surface-exposed targets. However, comparative genomics has identified prophage-like elements in several Treponema species, while the T. pallidum-lineage genomes examined by Ridgway et al. did not contain detectable prophage regions. This shifts the rationale from endogenous T. pallidum prophage exploitation toward cautious evaluation of heterologous treponemal phage-derived modules, with cross-species target compatibility as a central requirement. This review critically evaluates phage-derived strategies against T. pallidum, discussing biological barriers, prophage genomics, candidate modalities, biosafety filters, and regulatory considerations. We propose a staged translational roadmap progressing from evidence appraisal and candidate prioritization to biochemical validation, direct T. pallidum testing, ex vivo assessment, in vivo validation, and product-class-specific development. Currently, the most credible outputs of this field are research tools, diagnostic binding modules, and early antimicrobial prototypes rather than clinical phage therapy for syphilis.