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Fusidic acid is a translation inhibitor with activity against major Gram-positive bacterial pathogens such as S. aureus. However, its activity against Gram-negatives is poor based on an inability to access its cytoplasmic target in these organisms. Opportunities for functionalization of the fusidic acid scaffold to enhance activity against Gram-negative pathogens have not been explored. Using an activity-guided synthetic strategy, the tolerance of the tetracyclic natural product to derivatization at the A- and C-rings and its carboxylic acid side chain was explored with the goal of enhancing its activity spectrum and pharmacological properties. All side-chain carboxylic acid esters were inactive. Oxidation of the C-ring alcohol and oxime were not tolerated either. A number of esters of the A-ring alcohol retained modest activity against Gram-positive bacteria and were informative for future activity-guided studies. For the A-ring esters, differences in antibacterial activity relative to inhibitory activity in a ribosome in vitro translation assay suggested the possibility of a pro-druglike effect for the fusidic acid pyrazine-2-carboxylate. This study furthers the understanding of the activity of the fusidic acid scaffold against Gram-positive bacteria. These results suggest promise for future modification of the A-ring alcohol of fusidic acid in the advancement of its antibiotic properties. 

Emerging resistance to all classes of antimicrobials is one of the defining crises of the 21st century. Many advances in modern medicine, such as routine surgeries, are predicated on sustaining patients with antimicrobials during a period when their immune systems alone cannot clear infection. The development of new antimicrobials has not kept pace with the antimicrobial resistance (AR) threat. AR bacteria have been documented in various environments, such as drinking and surface water, food, sewage, and soil, yet surveillance and sampling has largely been from infected patients. The prevalence and diversity of AR bacteria in the environment, and the risks they pose to humans are not well understood. There is consensus that environmental surveillance is an important first step in forecasting and targeting efforts to prevent spread and transmission of AR microbes. However, efforts to date have been limited. The Prevalence of Antibiotic Resistance in the Environment (PARE) is a classroom-based project that engages students around the globe in systematic environmental AR surveillance with the goal of identifying areas where prevalence is high. The format of PARE, designed as short classroom research modules, lowers common barriers for institutional participation in course-based research. PARE brings real-world microbiology into the classroom by educating students about the pressing public health issue of AR, while empowering them to be partners in the solution. In turn, the PARE project provides impactful data to inform our understanding of the spread of AR in the environment through global real-time surveillance.