The diverse pioneer microbial community colonizing the mammalian gastrointestinal tract is critical for the developing immune system. Gut microbial communities of neonates can be affected by various internal and external factors, resulting in microbial dysbiosis. Microbial dysbiosis during early life affects gut homeostasis by changing metabolic, physiological, and immunological status, which increases susceptibility to neonatal infections and long-term pathologies. Early life is crucial for the establishment of microbiota and the development of the host immune system. Therefore, it provides a window of opportunity to reverse microbial dysbiosis with a positive impact on host health. Recent attempts to use microbial interventions during early life have successfully reversed dysbiotic gut microbial communities in neonates. However, interventions with persistent effects on microbiota and host health are still limited. This review will critically discuss microbial interventions, modulatory mechanisms, their limitations, and gaps in knowledge to understand their roles in improving neonatal gut health.

Background/Objectives: Osteomyelitis and implant-associated bone infections remain difficult to treat because of persistent bacterial colonization, biofilm formation, limited antibiotic exposure in infected bone, and antimicrobial resistance. Bisphosphonate conjugation has been explored for bone-targeted antibiotic delivery, but targeting a β-lactamase inhibitor itself to our knowledge has not been established. This study aimed to synthesize and evaluate an ester-linked bisphosphonate–tazobactam (BP-Tazo-ester) conjugate as a putative bone-targeted β-lactamase inhibitor prodrug. Methods: BP-Tazo-ester (compound 5) was synthesized and characterized by nuclear magnetic resonance spectroscopy and mass spectrometry. β-lactamase inhibition was assessed using a nitrocefin-based in vitro assay. Hydroxyapatite binding was evaluated using a sample derived from compound 5. Piperacillin combinations were evaluated against β-lactamase-producing Escherichia coli HS and planktonic Staphylococcus aureus CCUG 25925. The same S. aureus strain was used in an ex vivo bone-slice early-colonization model. Results: Compound 5 was obtained in 61% yield and retained measurable β-lactamase inhibitory activity, although its observed activity was lower than that of free tazobactam. TMSBr-treated material derived from compound 5 exhibited high apparent hydroxyapatite binding. Compound 5 supported piperacillin-mediated growth inhibition against E. coli HS. Against S. aureus CCUG 25925, piperacillin–compound 5 and piperacillin–tazobactam showed the same observed MIC, both lower than that of piperacillin alone, while compound 5 alone exhibited limited antibacterial activity. In the bone-slice model, piperacillin–compound 5 reduced recoverable S. aureus counts below the assay limit of detection during 24 h of treatment co-initiated with inoculation. Conclusions: These findings provide preliminary proof-of-concept for a bisphosphonate-based strategy targeting a β-lactamase inhibitor rather than the antibiotic partner. Further research on linker-cleavage kinetics, bone biodistribution, pharmacokinetics, and in vivo efficacy is warranted.