{'fraction_non_alphanumeric': 0.01631878557874763, 'fraction_numerical': 0.0, 'mean_word_length': 5.846753246753247, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Bisphosphonated Benzoxazinorifamycin Prodrugs for the Prevention and Treatment of Osteomyelitis

Osteomyelitis represents a challenge to modern medicine. This inflammatory process is accompanied by bone necrosis, and results from an underlying microbial infection primarily caused by Staphylococcus aureus. It is routinely treated by a combination of surgical debridement and a heavy and prolonged course of parenterally administered antibiotics. Frequent relapses are observed, and sometimes amputations are required. In general, osteomyelitis is established as a result of trauma, bone surgery, or joint replacement, and in cases of decreased vascularization, such as in diabetic and elderly patients. None of the antibiotics marketed in the United States have been approved for Gram-positive osteomyelitis ; as such, it represents a clear medical need. The sheltered environment provided by necrotic bone and the likely quiescent state of bacteria found in such sequestra are clear hurdles that require antibacterial agents to be administered in large doses to achieve a satisfactory therapeutic outcome. To avoid the systemic administration of large amounts of antibiotics, polymeric or mineral beads impregnated with antibiotics have been proposed in order to concentrate the therapeutic agent at the site of infection. Unfortunately, these materials must be surgically inserted, resulting in significant inconveniences in the context of a disease for which recurrences are common and repeat treatments are often required. Drug delivery to bone by way of systemic administration would present clear advantages in this case. Bisphosphonates, pyrophosphate analogues with strong, near-irreversible affinity to hydroxyapatite, the calcium phosphate bone mineral, have been used to deliver small-molecule therapeutics, ligands for radioisotope imaging, and even proteins to bone. Given their efficiency in this process, bisphosphonates would appear to be ideal targeting agents for the delivery of antibacterial agents to bone. Although a ciprofloxacin–bisphosphonate conjugate with demonstrated high affinity for bone has been synthesized, the bisphosphonate moiety in this strategy is likely to remain tethered to the antibiotic. As such, it would predictably immobilize ciprofloxacin irreversibly to the bone, thereby preventing it from accessing its intracellular target, bacterial topoisomerase. In contrast, a prodrug strategy uses bisphosphonates to direct antibiotics to bone but allows for their release at the site of infection and access to their pharmacological target. Bisphosphonated prodrugs have been described for the