Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI).

Francisella tularensis, the causative agent of tularemia, presents a significant biological threat and is a Category A priority pathogen due to its potential for weaponization. The bacterial FASII pathway is a viable target for the development of novel antibacterial agents treating Gram-negative infections. Here we report the advancement of a promising series of benzimidazole FabI (enoyl-ACP reductase) inhibitors to a second-generation using a systematic, structure-guided lead optimization strategy, and the determination of several co-crystal structures that confirm the binding mode of designed inhibitors. These compounds display an improved low nanomolar enzymatic activity as well as promising low microgram/mL antibacterial activity against both F. tularensis and Staphylococcus aureus and its methicillin-resistant strain (MRSA). The improvements in activity accompanying structural modifications lead to a better understanding of the relationship between the chemical structure and biological activity that encompasses both enzymatic and whole-cell activity.

US clinicians' perspectives on how mifepristone regulations affect access to medication abortion and early pregnancy loss care in primary care.

OBJECTIVE: Protocols including mifepristone are the most effective medication regimens for medication abortion and early pregnancy loss (EPL) management. Both can be safely and effectively offered in primary care settings. Despite mifepristone's excellent safety record, the United States (US) Food and Drug Administration (FDA) heavily regulates provision. This exploratory study examines US primary care clinicians' perspectives on the effects of mifepristone restrictions, including FDA regulations, on access to medication abortion and EPL management in primary care. STUDY DESIGN: In 2019, we conducted an online qualitative survey of US primary care clinicians recruited from six reproductive health-focused listservs. Open-ended questions queried about barriers to providing mifepristone and effects on patients when unable to access mifepristone in primary care. We iteratively coded and analyzed qualitative data using inductive thematic analysis. RESULTS: Of our analytic sample of 113 respondents, one-third had mifepristone available in their current primary practice setting. Key barriers to provision stemmed from the FDA rule to stock and dispense mifepristone onsite, including logistical difficulties and resistance from health center leadership. Clinicians believed that lack of mifepristone in primary care resulted in negative patient experiences, including disrupted continuity of care, medically-unnecessary appointments, and undesired aspiration procedures. CONCLUSIONS: FDA regulations that inhibit mifepristone provision in primary care create structural barriers to provision. This may result in physical, emotional, and financial burdens for patients. IMPLICATIONS: When mifepristone is unavailable in primary care, some patients in need of abortion or EPL care may experience physical, emotional, and financial harms. Removing FDA restrictions is a critical step in reducing primary care barriers to mifepristone provision and improving access to timely, patient-centered medication abortion and EPL care.